Methods and apparatus for improved administration of analgesics

ABSTRACT

Methods and apparatus for improving administration of drugs through the use of heat and other physical means. The present invention relates to the use of heat and other physical means in conjunction with specially designed dermal drug delivery systems, conventional commercial dermal drug delivery systems, or drugs delivered into a sub-skin depot site via injection and other methods to alter, mainly increase, the drug release rate from the dermal drug delivery systems or the depot sites to accommodate certain clinical needs.

RELATED APPLICATIONS

[0001] The present application is claims priority to U.S. patentapplication Ser. No. 09/878,558 filed Jun. 11, 2001 to Jie Zhang et al.entitled Controlled Heat Induced Rapid Delivery of Pharmaceuticals fromSkin Depot which is a continuation in part application of U.S. patentapplication Ser. No. 09/162,587, to Jie Zhang et al. entitled filed Sep.29, 1998 for Methods and Apparatus for Improved Administration ofFentanyl and Sufentanil to Jie Zhang et al.; and which is also acontinuation-in-part of U.S. patent application Ser. No. 09/545,496filed Apr. 7, 2000, to Jie Zhang et al. and entitled Apparatus andMethods for Improved Administration of Fentanyl Pharmaceuticals, whichis a divisional application of U.S. patent application Ser. No.09/162,890 filed Sep. 29, 1998 to Jie Zhang et al. entitled Apparatusand Methods for Improved Noninvasive Dermal Administration ofPharmaceuticals patent number now issued as U.S. Pat. No. 6,245,347,which is a continuation-in-part of U.S. patent application Ser. No.08/819,880 filed Mar. 18, 1997 to Jie Zhang et al. entitled NoninvasiveDermal Anesthetics patent number now issued as U.S. Pat. No. 5,919,479which is a divisional of U.S. patent application Ser. No. 08/508,463filed Jul. 28, 1995 to Jie Zhang et al. entitled Apparatus and Methodsfor Improved Noninvasive Dermal Administration of Pharmaceuticals patentnumber now issued as U.S. Pat. No.5,658,583.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to methods and apparatus foradministration of drugs. More particularly, the present inventionrelates to using controlled heat and other physical means to improvedermal, mucosal, and injection administration of drugs.

[0004] 2. State of the Art

[0005] The dermal administration of pharmaceutically active compoundsinvolves the direct application of a pharmaceutically activeformulation(s) to the skin, wherein the skin absorbs a portion of thepharmaceutically active compound which is then taken up by the bloodstream. Such administration has long been known in the practice ofmedicine and continues to be an important technique in the delivery ofpharmaceutically active compounds. For example, U.S. Pat. No. 4,286,592issued Sep. 1, 1981 to Chandrasekaran shows a bandage for administeringdrugs to a user's skin consisting of an impermeable backing layer, adrug reservoir layer composed of a drug and a carrier, and a contactadhesive layer by which the bandage is affixed to the skin.

[0006] Such dermal administration offers many important advantages overother delivery techniques, such as injection, oral tablets and capsules.These advantages include being noninvasive (thus, less risk ofinfection), avoiding first pass metabolism (metabolism of the drug inthe liver when the drug is taken orally and absorbed through thegastrointestinal tract), and avoiding of high peaks and low valleys ofconcentration of pharmaceutically active compounds in a patient'sbloodstream. In particular, high peaks and low valleys of concentrationare typical in injection and oral administrations and are oftenassociated with undesirable side effects and/or less than satisfactoryintended effects.

[0007] The term “dermal drug delivery system” or “DDDS”, as used herein,is defined as an article or apparatus containing pharmaceutically activecompound(s) for delivery into the skin, the regional tissues under theskin, the systemic circulation, or other targeting site(s) in a humanbody via skin permeation. The term “DDDS” in this application, unlessotherwise specified, only refer to those systems in which the maindriving force for drug permeation is the drug concentration gradient.

[0008] The term “skin”, as used herein, is defined to include stratumcorneum covered skin and mucosal membranes.

[0009] The term “drug”, as used herein, is defined to include anypharmaceutically active compound including but not limited to compoundsthat treat diseases, injuries, undesirable symptoms, and improve ormaintain health.

[0010] The terms “targeted area” or “targeted areas”, as used herein,are defined to include a systemic bloodstream of a human body, areas ofa human body which can be reached by a systemic bloodstream including,but not limited to muscles, brain, liver, kidneys, etc., and body tissueregions proximate a location of an administered drug.

[0011] In DDDSs, a drug(s) is usually contained in a formulation, suchas a hydro-alcohol alcohol gel, and may include a rate limiting membranebetween the formulation and skin for minimizing the variation in thepermeation of the drug. When a DDDS is applied to skin, the drug beginsto transport out of the formulation, and transport across the ratelimiting membrane (if present). The drug then enters the skin, entersblood vessels and tissues under the skin, and is taken into the systemiccirculation of the body by the blood. At least some DDDSs have certainamount of pharmaceutically active compound in or on the skin side of therate limiting membrane (if present) prior to use. In those DDDSs, thatportion of the drug on the skin side of the rate limiting membrane willenter the skin without passing through the rate limiting membrane. Formany drugs, a significant portion of the dermally absorbed drug isstored in the skin and/or tissues under the skin (hereinafter referredas “depot sites”) before being gradually taken into the systemiccirculation (hereinafter referred as “depot effect”). This depot effectis believed to be at least partially responsible for the delayedappearance of the drug in the systemic circulation after the applicationof some DDDSs and for continued delivery of the drug into the systemiccirculation after the removal of some DDDSs from the skin.

[0012] After placing a DDDS on the skin, the drug concentration in theblood typically remains at or near zero for a period of time, beforestarting to gradually increase and reach a concentration deemed to bemedicinally beneficial, called the “therapeutic level” (the time ittakes to reach the therapeutic level is referred to hereinafter as the“onset time”). Ideally, the concentration of the drug in the bloodstreamshould plateau (i.e., reach a substantially steady state) at a levelslightly higher than the therapeutic level and should remain there forextended period of time. For a given person and a given DDDS, the“concentration of the drug in the bloodstream vs. time” relationshipusually cannot be altered under normal application conditions.

[0013] The onset time and the delivery rate of the drug into thetargeted area(s) of the body for a typical DDDS are usually determinedby several factors, including: the rate of release of the drug from theformulation, the permeability of the drug across the rate limitingmembrane (if a rate limiting membrane is utilized), the permeability ofthe drug across the skin (especially the stratum corneum layer), drugstorage in and release from the depot sites, the permeability of thewalls of the blood vessels, and the circulation of blood and other bodyfluid in the tissues (including the skin) under and around the DDDS.Although these primary factors affecting onset time and delivery rateare known, no existing DDDS is designed to have alterable delivery ratein the course of the application of the drug.

[0014] While a DDDS works well in many aspects, current dermal drugdelivery technology has some serious limitations, including: 1) theonset time being undesirably long for many DDDSs; 2) the rate that thedrug is taken into the systemic circulation or the targeted area(s) ofthe body cannot be easily varied once the DDDS is applied onto the skinand, when the steady state delivery rate is achieved, it cannot beeasily changed; and 3) the skin permeability being so low that manydrugs are excluded from dermal delivery because the amount of drugdelivered is not high enough to reach a therapeutic level. In addition,temperature variations in the skin and the DDDS are believed contributeto the variation of dermal absorption of drugs.

[0015] It is known that elevated temperature can increase the absorptionof drugs through the skin. U.S. Pat. No. 4,898,592, issued Feb. 6, 1990to Latzke et al., relates to a device for the application of heatedtransdermally absorbable active substances which includes a carrierimpregnated with a transdermally absorbable active substance and asupport. The support is a laminate made up of one or more polymericlayers and optionally includes a heat conductive element. This heatconductive element is used for distribution of the patient's body heatsuch that absorption of the active substance is enhanced. U.S. Pat. No.4,230,105, issued Oct. 28, 1980 to Harwood, discloses a bandage with adrug and a heat-generating substance, preferably intermixed, to enhancethe rate of absorption of the drug by a user's skin. Separate drug andheat-generating substance layers are also disclosed. U.S. Pat. No.4,685,911, issued Aug. 11, 1987 to Konno et al., discloses a skin patchincluding a drug component, and an optional heating element for meltingthe drug-containing formulation if body temperature is inadequate to doso.

[0016] Another area of administration involves delivering drugs incontrolled/extended release form/formulations (“form/formulation”) intothe skin or tissues under the skin (the residing place for theseform/formulations are hereinafter referred as “storage sites”) whichresults in the drugs being released from the storage sites in acontrolled/extended fashion. The most common technique to deliver theform/formulations into the storage sites is by injection. Othertechniques may also be used, such as implantation and forcing theform/formulation into the skin with high-speed hitting. However, oncethe form/formulation is delivered into the storage sites, it is usuallydifficult to alter the rate, known as the “release rate”, that the drugis released from the form/formulation at the storage sites, and takeninto the systemic circulation or the targeted area(s) of the body.

[0017] Yet another area of administration involves injecting drugssubcutaneously or intramuscularly. In some clinical situations, it isbeneficial to accelerate the speed of drug absorption into the systemiccirculation or other targeted areas(s) in the body after such injection.

[0018] Therefore, it would be advantageous to develop methods andapparatus to improve the drug administration of DDDSs, and, morespecifically, to make the use of DDDSs more flexible, controllable, andtitratable (varying the drug delivery rate, amount, or period accordingto the biological effect of the drug) to better accommodate variousclinical needs. It would also be advantageous to develop methods andapparatus to make dermal delivery possible for drugs which are currentlyexcluded because of low skin permeability. It would further beadvantageous to develop means to alter mainly to increase the drugabsorption rate from the storage sites or injection sites in such waysthat can accommodate certain clinical needs.

SUMMARY OF THE INVENTION

[0019] The present invention relates to various methods and apparatusfor improved dermal and mucosal administration of drugs through the useof controlled heat and other physical means. The present inventionfurther relates to methods and apparatus for using controlled heat andother physical means to alter, mainly increase, the drug release ratefrom the storage sites or injection sites in such ways to accommodatecertain clinical needs.

[0020] In the application of a DDDS, the absorption of the drug isusually determined by a number of factors including: the diffusioncoefficient of drug molecules in the drug formulation, the permeabilitycoefficient of the drug across the rate limiting membrane (if one isused in the DDDS), the concentration of dissolved drug in theformulation, the skin permeability of the drug, drug storage in andrelease from the depot sites, the body fluid (including blood)circulation in the skin and/or other tissues under the skin, andpermeability of the walls of capillary blood vessels in the sub-skintissues. Thus, in order to address the limitations of the current dermaldrug delivery technologies, it is desirable to have control over andhave the capability to alter these drug absorption factors. It isbelieved that controlled heating/cooling can potentially affect each oneof the above factors.

[0021] Specifically, increased temperature generally can increasediffusion coefficients of the drugs in the formulations and theirpermeability across the rate limiting membrane and skin. Increased heatalso increases the blood and/or other body fluid flow in the tissuesunder the DDDS, which should carry the drug molecules into the systemiccirculation at faster rates. Additionally, increased temperature alsoincreases the permeability of the walls of the capillary blood vesselsin the sub-skin tissues. Furthermore, increased temperature can increasethe solubility of most, if not all, drugs in their formulations which,in formulations with undissolved drugs, should increase permeationdriving force. Of course, cooling should have substantially the oppositeeffect. Thus, the present invention uses controlled heating/cooling toaffect each of the above factors for obtaining controllable dermalabsorption of drugs.

[0022] The present invention also uses controlled heating/cooling inseveral novel ways to make dermal drug delivery more flexible and morecontrollable in order to deal with various clinical conditions and tomeet the needs of individual patients. More broadly, this inventionprovides novel methods and apparatus for controlled heating/cooling(hereinafter “temperature control apparatus”) during the application ofthe DDDS, such that heating can be initiated, reduced, increased, andstopped to accommodate the needs.

[0023] Another embodiment of the present invention is to determine theduration of controlled heating on DDDS based on the effect of the drugfor obtaining adequate amount of the extra drug and minimizingunder-treatment and side effects associated with under and over dosing.

[0024] Through the proper selection, based on the specific applicationand/or the individual patient's need, of the moment(s) to initiatecontrolled heating, heating temperature, and moment(s) to stop thecontrolled heating, the following control/manipulation of the absorptionrates should be achieved: 1) shorten the onset time of the drug in theDDDS without significantly changing its steady state delivery rates; 2)provide proper amount of extra drug during the application of a DDDSwhen needed; and 3) increase the drug absorption rate throughout asignificant period of duration or throughout the entire duration of theDDDS application.

[0025] Shortening of onset time is important in situations where theDDDS provides adequate steady state deliver rates, but the onset is tooslow. Providing the proper amount of extra drug is important where aDDDS delivers adequate “baseline” amount of the drug, but the patientneeds extra drug at particular moment(s) for particular period(s) oftime during the application of the DDDS. Increasing the drug absorptionrate is used for the patients who need higher drug delivery rates fromthe DDDS.

[0026] The first of above approach can be achieved by applyingcontrolled heating at the starting time of the DDDS application, anddesign the heating to last long enough to cause the concentration of thedrug in the systemic circulation or other targeted area of the body torise toward the therapeutic levels, and stops (may be gradually) shortlyafter that. The second approach may be achieved by applying controlledheat when a need to obtain extra drug are rises, and terminating thecontrolled heating either at a predetermined moment or when the desiredeffect of the extra drug is achieved. The third approach can be achievedby applying the controlled heat at the starting time of the DDDSapplication. In all those three approaches, temperature of thecontrolled heating needs to be designed to control the degree ofincrease in said that drug delivery rates.

[0027] Such embodiments are particularly useful in situations where theuser of a DDDS gets adequate drug absorption most of the time, but thereare periods of time in which increased or decreased drug absorption isdesirable. For example, during the treatment of cancer patients with ananalgesic, such as with Duragesic® dermal fentanyl patches (distributedby Janssen Pharmaceutica, Inc. of Piscataway, New Jersey, USA),“breakthrough” pain (a suddenly increased and relatively short lastingpain, in addition to a continuous “baseline” pain) may occur. Anadditional analgesic dose, in the form of a tablet, an oral or nasalmucosal absorption dosage form, or an injection needs to be given totreat the breakthrough pain. But with the help of controlled heat, onesingle DDDS may take care of both baseline pain and episodes ofbreakthrough pain. With the help of controlled heat, a heating patch canbe placed on top of the Duragesic® patch when an episode of breakthroughpain occurs to deliver more fentanyl into the systemic circulation. Theheating duration of the heating patch is preferably designed to be longenough to deliver sufficient extra fentanyl, but not long enough todeliver the extra amount of fentanyl that may pose a risk to thepatient. The patient may also remove the heating patch when thebreakthrough pain begins to diminish. Thus, with the help of controlledheat, one single Duragesic® dermal fentanyl patch may take care of bothbaseline pain and episodes of breakthrough pain. For another example, adermal nicotine patch user may obtain extra nicotine for a suddenlyincreased nicotine craving by heating the nicotine patch.

[0028] Due to low skin permeability of the skin, onset times ofconventional DDDSs are usually quite long, and often undesirably long.Thus, another aspect of the present invention is to provide methods andapparatus for using controlled heat to shorten the onset times of DDDSs,preferably without substantially changing the steady state drug deliveryrates. A particularly useful application of this aspect of the presentinvention is to provide a controlled heating apparatus for use withconventional, commercially available DDDSs to shorten the onset times inclinical use, without having to re-design the DDDSs or adjust theirsteady state drug delivery rates.

[0029] It is believed that an important cause for variation in drugabsorption in DDDSs is variation in temperature of the DDDSs and theadjacent skin caused by variations in ambient temperature and/orphysical condition of the person. This temperature variation can, ofcourse, potentially affect all of the factors that collectivelydetermine the ultimate drug delivery rates of the DDDSs. Thus, thepresent invention of providing methods and apparatus to use controlledheating/cooling also minimizes the variation in temperature of the skinand the DDDSs applied on the skin. It is also contemplated that aninsulating material can be incorporated with the controlled temperatureapparatus to assist in not only minimizing the temperature variation,but also increasing the temperature of the DDDS and the skin under it(by decreasing heat loss), each of which tend to increase dermal drugabsorption.

[0030] The present invention also relates to methods and apparatus forusing an insulating device, such as a cover made of insulating material(such as closed-cell foam tape) with adhesive edges, and a size slightlylarger than the DDDS or the area over an injected drug, to cover theDDDS/injected drug when the DDDS and/or the skin of the user is exposedto extreme temperature (such as a hot shower or bath, direct sunlight,etc.).

[0031] An important area in modem anesthesiology is patient controlledanalgesia (hereinafter “PCA”), in which the patient gives himself a doseof analgesic when he feels the need. The ranges of the dose and dosingfrequency are usually set by a care giver (i.e., caring physician,nurse, etc.). In many PCA situations, the patient receives a baselinerate of analgesic, and gets extra bolus analgesic when he feels that itis needed. The technology in the present invention may be used for a PCAin which the patient gets the baseline dose by a regular dermalanalgesic patch and the extra (“rescue”) dose by heating the dermalanalgesic patch. The heating temperature and duration needs to bedesigned to deliver a proper amount of extra dose.

[0032] Drugs in controlled or extended release forms or formulations maybe delivered into depot/storage sites in the skin and/or the tissuesunder the skin with methods such as injection, implantation, hitting thedrug/drug formulation on the skin with supersonic speed, and embeddingthe drug/drug formulation onto the skin. The controlled/extendedform/formulation allows the drug to be released gradually into thesurrounding tissues and/or systemic circulation over an extended periodof time. For instance, extended release insulin (such as Ultralente®zinc insulin -Eli Lilly and Co.) can be injected subcutaneously todeliver insulin into the patient's systemic circulation over an extendedperiod of time. However, once the drug in the controlled/extendedform/formulation is delivered to the storage sites, it is usuallydifficult to alter or control the course of drug release. The apparatusand methods of the present invention allow controlled heat to increaseand controlled cooling to decrease, the drug release from thecontrolled/extended form/formulation after it is delivered into thedepot/storage sites. For example, many diabetic patients need additionalinsulin shortly before meals to suppress the blood sugar increaseresulting from the meals. However, the release rate of thesubcutaneously injected extended release insulin is relatively constant.With the methods and apparatus in the invention, a diabetic patient mayinject a subcutaneous extended release insulin in the morning and applycontrolled heat on the skin of the injection site for a duration of timeshortly before ingestion of a meal to obtain additional insulin tosuppress the sugar from the meal. The controlled heat increases the flowof blood and other body fluid surrounding the storage sites and isbelieved to increase the dissolution rate of insulin. It is, of course,understood that whether a given controlled/extended release formulationin the depot/storage sites can actually release extra drug withincreased temperature depends on the nature of the drugform/formulation. However, since heat is known or expected to increasethe diffusion speed of drugs in their formulations, increase thepermeability of blood vessel walls, and increases the circulation ofbody fluid surrounding the depot sites, each of which tend to favorincreased drug release, the heat-induced extra drug release is expectedto take place for many, if not most, controlled/extended drugform/formulation delivered into sub-skin storage sites.

[0033] One important aspect of the present invention is to properlychoose the temperature of the controlled heat and the moment(s) toinitiate and stop the controlled heat in the applications with injecteddrug formulations, especially extended/controlled release formulations,to accommodate the needs of different therapies and individual patients,in ways similar to the applications with DDDSs discussed above.

[0034] Many biodegradable polymers may be used to makecontrolled/extended release formulations. Of particular note are thebiogradable lactic/glycolic acid polymers described in Chapters 29 and33 of Encyclopedic Handbook of Biomaterials and Bioengineering, editedby Donald L. Wise, et al., publ. Marcel Dekker, 1995, herebyincorporated herein by reference. It is one important aspect of thepresent invention to use controlled heat, as discussed above, tocontrol/regulate drug release rates from controlled/extended releaseformulations made with such polymers, and preferably, prepared using themethods described in the Encyclopedic Handbook of Biomaterials andBioengineering.

[0035] For drugs where quick systemic absorption is important, thepresent invention may be beneficial. For example, it is generally agreedthat to successfully treat a migraine headache, concentrations of ananti-migraine drug, such as dihydroergotamine, in the bloodstream mustreach a therapeutic level within a certain time from the onset ofmigraine headache. In such situations, the heating devices, as discussedabove, may be used with normal injection of drugs. Since heat canusually increase the diffusion speed of drugs in their formulations,increase the permeability of blood vessel walls, and increases thecirculation of body fluid surrounding the injection site, the drug willenter the system circulation more quickly.

[0036] One of the more important aspects of the present invention is theapparatus for generating and providing controlled heating. Thesecontrolled heat generating apparatus generally comprise a heatgenerating portion and a means to pass the heat generated by the heatgenerating portion to the DDDSs, the skin, and/or the sub-skin depot andstorage sites. These controlled heat generating apparatus generallyfurther include a mechanism (such as tape, adhesive, and the like) foraffixing apparatus onto the DDDSs and/or the skin. Preferably, theaffixation mechanism securely holds the controlled heat generatingapparatus in place while in use, but it also allows relatively easyremoval after use. Additionally, these controlled heat generatingapparatus may further include a mechanism for terminating the generationof heat. The shape and size of the bottom of the controlled heatgenerating apparatus are generally specially made to accommodate theDDDSs with which they are to be employed.

[0037] One embodiment of a controlled heat generating apparatus is ashallow chamber including non-air permeable side wall(s), a bottom wall,and a non-air permeable top wall which has area(s) with limited anddesired air permeability (e.g., holes covered with a microporousmembrane). A heat generating medium is disposed within the shallowchamber. The heat generating medium preferably comprises a mixture ofiron powder, activated carbon, salt, water, and, optionally, sawdust.The controlled heat generating apparatus is preferably stored in anair-tight container from which it is removed prior to use. After removalfrom the air-tight container, oxygen in the atmosphere (“ambientoxygen”) flows into heat generating medium through the areas on thenon-air permeable top with desired air-permeability to initiate a heatgenerating oxidation reaction (i.e., an exothermic reaction). Thedesired heating temperature and duration can be obtained by selectingthe air exposure of the top (e.g., selecting the right size and numberof holes on the cover and/or selecting the microporous membrane coveringthe holes for a specific air permeability), and/or by selecting theright quantities and/or ratios of components of the heat generatingmedium.

[0038] This embodiment of the controlled heat generating apparatuspreferably includes a mechanism for affixing the controlled heatgenerating apparatus onto the skin or a DDDS that is applied to theskin. For applications where the removal or termination of the heatingmight be necessary, the heat generating apparatus may also have amechanism for allowing easy removal from the DDDS and/or the skin or fortermination of the heating. One mechanism for allowing easy removal ofthe shallow chamber from a DDDS without removing the latter from theskin comprises a layer of adhesive on the side walls of the heatgenerating apparatus with an non-adhesive area or less adhesive area(less adhesive than the adhesive affixing the DDDS to the skin) at thebottom of the shallow chamber, with the non- or less adhesive areahaving a shape similar to that of the DDDS. When such a heat generatingapparatus is applied onto the DDDS which is on the skin, the adhesive atthe bottom of the side walls of the heat generating apparatus adheres tothe skin, and non- or less adhesive part is on top of, but not adheredor not strongly adhered to, the DDDS. This allows for removal of theheat generating apparatus without disturbing the DDDS.

[0039] Although one application of such a heat generating apparatus isto be used in conjunction with a DDDS, it is understood that the heatgenerating apparatus can also be applied directly to the skin toincrease the release of drugs from depot sites or sites of injection orimplantation of controlled released drugs (storage sites), or toaccelerate the absorption of subcutaneously or intramuscularly injecteddrugs.

[0040] The heat generating mechanism of the present invention for thecontrolled heat generating apparatus is not limited to the preferredexothermic reaction mixture of iron powder, activated carbon, salt,water, and, optionally, sawdust, but may include a heating unit whoseheat is generated by electricity. The electric heating unit, preferably,includes a two dimensional surface to pass the heat to the DDDS and/orthe skin. The electric heating unit may also include a temperaturefeedback system and a temperature sensor that can be placed on the DDDSor the skin. The temperature sensor monitors the temperature at the DDDSor skin and transmits an electric signal based on the sensed temperatureto a controller which regulates the electric current or voltage to theelectric heating unit to keep the temperature at the DDDS or skin atdesired levels. Preferably, a double sided adhesive tape can be used toaffix the electric heating unit onto the skin.

[0041] The heat generating mechanism may also comprise an infraredgenerating unit and a mechanism to direct the infrared radiation ontothe DDDS or the skin. It may also have a temperature feedback system anda temperature sensor that can be placed on the DDDS or the skin tocontrol the intensity of the infrared emission to maintain thetemperature at the DDDS or skin at desired levels.

[0042] The heat generating mechanism may further comprise a microwavegeneration unit and a mechanism to direct the microwave radiation ontothe DDDS or the skin. Again, the heat generating mechanism may have atemperature feedback system and a temperature sensor to regulate theintensity of the microwave emission to maintain the temperature at theDDDS or skin at desired levels.

[0043] The heat generating mechanism may yet further comprise acontainer containing supercooled liquid which generates heat fromcrystallization (“exothermic”). The crystallization is initiated withinthe container, such as by bending a metal piece in the supercooledliquid, and the container is placed on a DDDS or on the skin. The heatwhich is released from the crystallization process is passed to the DDDSand/or the skin. However, heat generated by crystallization usually doesnot maintain a constant level over extended time. Thus, such a heatgenerating mechanism is not ideal for applications where elevatedtemperature in a narrow range over an extended time is necessary, but isuseful where only a short heating duration is needed, such as with aDDDS that would benefit from short heating duration to minimize theonset time.

[0044] Although, in general, most benefits for DDDSs are realized fromincreased drug absorption and release rates by heating, there arecircumstances where it may be desirable to be able to both increase anddecrease the drug absorption and release rates. It is understood thatfor a more complete control in dermal and controlled/extended releasedrug administration that a mechanism for providing both heating orcooling, depending on need, would be advantageous. Thus, a novelapproach of this invention is to provide methods and apparatus forproviding heating or cooling to the DDDSs, the skin and/or the tissuesunder it, or the controlled/extended release drug form/formulation inthe skin or the tissues under the skin, such that the drug absorptionand/or release can be controlled. The heating/cooling mechanismcomprises a thermoelectric module which functions as a heat pump whereinthe power supply may be reversed depending on whether heating or coolingis desired. A cooling mechanism can include an endothermiccrystallization mechanism similar to the exothermic crystallizationmechanism discussed above.

[0045] It is, of course, understood that the use of controlled heatingand/or cooling to control drug absorption and/or release are equallyapplicable to controlled/extended form/formulations after they aredelivered into the skin and/or tissues under the skin. However, physicalmechanisms other than heating and/or cooling may also be used for thesame purpose. Thus, it is novel approach of this invention to providemethods and apparatus to use ultrasound, electric current, andmechanical vibration to induce extra drug release fromcontrolled/extended release form/formulations which are alreadydelivered into the body and that are responsive to these physicalinduction means.

BRIEF DESCRIPTION OF THE DRAWINGS

[0046] While the specification concludes with claims particularlypointing out and distinctly claiming that which is regarded as thepresent invention, the objects and advantages of this invention may bemore readily ascertained from the following description of theinvention, when read in conjunction with the accompanying drawings inwhich:

[0047]FIG. 1 is a side cross-sectional view of an embodiment of atemperature control apparatus according to the present invention;

[0048]FIG. 2 is a side cross-sectional view of another embodiment of atemperature control apparatus according to the present invention;

[0049]FIG. 3 is a side cross-sectional view of an embodiment of a dermaldrug delivery system according to the present invention;

[0050]FIG. 4 is a side cross-sectional view of the temperature controlapparatus of FIG. 2 in conjunction with the dermal drug delivery systemof FIG. 3 according to the present invention;

[0051]FIG. 5 is a graph of time versus temperature for a temperaturecontrol apparatus according to the present invention;

[0052]FIG. 6 is a graph of the mean fentanyl concentration of ninevolunteers verse time for a four hour contact of a fentanyl containingDDDS with heating and without heating according to the presentinvention;

[0053]FIG. 7 is a graph of time versus temperature for a temperaturecontrol apparatus according to the present invention;

[0054]FIG. 8 is a side cross-sectional view of another embodiment of atemperature control apparatus according to the present invention;

[0055]FIG. 9 is a side cross-sectional view of another embodiment of adermal drug delivery system according to the present invention;

[0056]FIG. 10 is a side cross-sectional view of the temperature controlapparatus of FIG. 8 in conjunction with the dermal drug delivery systemof FIG. 9 according to the present invention;

[0057]FIG. 11 is a side cross-sectional view of still another embodimentof a dermal drug delivery system according to the present invention;

[0058]FIG. 12 is a side cross-sectional view of the temperature controlapparatus of FIG. 8 in conjunction with the dermal drug delivery systemof FIG. 11 according to the present invention;

[0059]FIG. 13 is a side cross-sectional view of yet another embodimentof a temperature control apparatus having three cover layers over anoxygen activated temperature regulating mechanism chambers according tothe present invention;

[0060]FIG. 14 is a side cross-sectional view of the temperature controlapparatus of FIG. 13 having a first cover layer removed according to thepresent invention;

[0061]FIG. 15 is a top plan view of the temperature control apparatus ofFIG. 14 along line 15-15 according to the present invention;

[0062]FIG. 16 is a side cross-sectional view of the temperature controlapparatus of FIG. 14 having a second cover layer removed according tothe present invention;

[0063]FIG. 17 is a top plan view of the temperature control apparatus ofFIG. 16 along line 17-17 according to the present invention;

[0064]FIG. 18 is a side cross-sectional view of the temperature controlapparatus of FIG. 16 having a third cover layer removed according to thepresent invention;

[0065]FIG. 19 is a top plan view of the temperature control apparatus ofFIG. 18 along line 19-19 according to the present invention;

[0066]FIG. 20 is a side cross-sectional view of another embodiment of adermal drug delivery system having a rate limiting membrane according tothe present invention;

[0067]FIG. 21 is a side cross-sectional view of an electric temperaturecontrol mechanism according to the present invention;

[0068]FIG. 22 is a side cross-sectional view of a temperature controlapparatus comprising a flexible bag filled with a supercooled liquidaccording to the present invention;

[0069]FIG. 23 is a side cross-sectional view of a temperature controlapparatus capable of both heating and cooling applied to a DDDSaccording to the present invention;

[0070]FIG. 24 is a schematic for a closed loop temperature controllerfor the temperature control apparatus of FIG. 23 according to thepresent invention;

[0071]FIG. 25 is a side cross-sectional view of a temperature controlapparatus applied directly to a patient's skin according to the presentinvention;

[0072]FIG. 26 is a side cross-sectional view an electrical mechanism forincreasing drug absorption according to the present invention;

[0073]FIG. 27 is a side cross-sectional view a vibrational mechanism forincreasing drug absorption according to the present invention;

[0074]FIG. 28 is a side cross-sectional view of a temperature controlapparatus capable of both heating and cooling applied directly to apatient's skin according to the present invention; and

[0075]FIG. 29-32 is a side cross-sectional view an insulative materialover a DDDS and injected or depot drug sites for minimizing temperaturevariation and/or increasing the temperature of the DDDS and the skinthereunder according to the present invention.

DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENT

[0076] FIGS. 1-32 illustrate various views of temperature control orother apparatuses and dermal drug delivery systems. It should beunderstood that the figures presented in conjunction with thisdescription are not meant to be illustrative of actual views of anyparticular apparatus, but are merely idealized representations which areemployed to more clearly and fully depict the present invention thanwould otherwise be possible. Elements common between the figures retainthe same numeric designations.

[0077]FIG. 1 illustrates a temperature control apparatus 100 of thepresent invention comprising a chamber defined by a bottom wall 102, atop wall 104, and side walls 106 wherein a temperature regulatingmechanism 108 is disposed within the chamber. The temperature regulatingmechanism 108 can include a heat generating oxidation reactionmechanism, electric heating unit, exothermic crystallization mechanism,endothermic crystallization mechanism, heating/cooling mechanism,cooling mechanism, or the like.

[0078]FIG. 2 illustrates a temperature control apparatus 100 comprisinga temperature regulating mechanism 108 surrounded by a bottom wall 102,a top wall 104, and side walls 106. The bottom wall 102 is preferably aplastic material and the side walls 106 are preferably made of aflexible non-air permeable material, such as non-air permeableclosed-cell foam material. A portion or all of the bottom wall 102 ofthe temperature control apparatus 100 includes an adhesive material 112for attachment to a DDDS or to the skin of a patient. The temperatureregulating mechanism 108 preferably comprises a composition of activatedcarbon, iron powder, sodium chloride and water in a proper ratio.Optionally, saw dust may be added to the composition to facilitate theairflow within the composition and/or provide “body” to the composition.The top wall 104 is preferably also a flexible non-air permeablematerial having holes 114 therethrough. An air permeable membrane 116is, preferably, disposed between the top wall 104 and the temperatureregulating mechanism 108 to regulate the amount of air reaching thetemperature regulating mechanism 108 through the holes 114. The airpermeable membrane 116 is preferably a porous film (such as No. 9711microporous polyethylene film-CoTran™, 3M Corporation, Minneapolis,Minn., USA).

[0079]FIG. 3 illustrates a dermal drug delivery system 120 (hereinafter“DDDS 120”) comprising a housing 122 made of a flexible material(s). Thehousing 122 preferably comprises side walls 124 and a top wall 126 witha drug formulation 128 disposed within the housing 122. Preferably, thebottom of the DDDS side walls 124 include an adhesive 132 to affix theDDDS 120 to the skin of a patient.

[0080]FIG. 4 illustrates the temperature control apparatus 100 of FIG. 2attached to the DDDS 120 of FIG. 3. The DDDS 120 attached to a portionof the skin 134 of a patient. The area of the temperature regulatingmechanism 108 is preferably slightly larger than that of the drugformulation 128. The temperature control apparatus 100 and the DDDS 120are preferably stored in separated compartments of an air tightcontainer (or in separate air tight containers).

EXAMPLE 1

[0081] One example of using the embodiment of the present inventionillustrated in FIGS. 2-4 for administering analgesic material for reliefof pain consists of a patient or care giver placing the DDDS 120 on theskin 134 of the patient, which preferably adheres to the skin 134 withDDDS adhesive 132. The patient or care giver then attaches thetemperature control apparatus 100 on top of the DDDS 120, which adheresto the DDDS 120 with temperature control apparatus adhesive 112. Oxygenin ambient air flows into the temperature regulating mechanism 108through holes 114 and air permeable membrane 116. Of course, it isunderstood that the rate at which oxygen contacts the temperatureregulating mechanism 108 is determined by the size and number of theholes 114 on the top wall 104, as well as the air permeability of theair permeable membrane 116. A heat generating (exothermic) chemicalreaction occurs in the temperature regulating mechanism 108. Heat fromthis reaction passes through the temperature control apparatus bottomwall 102, through the DDDS top wall 126, through the drug formulation128, and increases the temperature of the patient's skin 134 under theDDDS 120.

[0082] In actual experimentation, the temperature control apparatus 100comprised the side walls 106 defined by a ⅛ inch thick rectangular foamtape (2 layers of No. 1779 1/16″ white foam tape, 3M Corporation,Minneapolis, Minn., USA) with an outer dimension of about 2.25 inches by4 inches with an opening therein having an inner dimension of about 1.75inches by 3.5 inches, the bottom wall 102 comprising rectangular medicaltape (No. 1525 L plastic medical tape, 3M Corporation, Minneapolis,Minn., USA) of a dimension of about 2.25 inches by 4 inches with anon-adhesive side attached to the bottom of the side walls 106, and atop wall 104 comprising a rectangular {fraction (1/32)} inch thick foamtape (No. 9773 1/32″ tan foam tape, 3M Corporation, Minneapolis, Minn.,USA) with forty-five holes 114 (diameters approximately 0.9 mm, in a 5by 9 pattern with about 7.5 mm to 8.0 mm center spacing) therethrough.The side walls 106, the bottom wall 102, and the top wall 104 defined achamber. The holes 114 of the top wall 104 were covered by an airpermeable membrane 116 comprising a porous membrane (No. 9711microporous polyethylene film—CoTran™, 3M Corporation, Minneapolis,Minn., USA) disposed between the top wall 104 and the temperatureregulating mechanism 108. The side walls 106, the bottom wall 102, andthe top wall 104 all had {fraction (1/8)}″rounded corners. Thetemperature regulating mechanism 108 disposed in the chamber comprised amixture of activated carbon (HDC grade—Norit Americas, Inc., USA), ironpowder (grade R1430-ISP Technologies, USA), saw dust (Wood Flour,Pine-Pioneer Sawdust, USA), sodium chloride and water in the weightratio of approximately 5:16:3:2:6 weighing approximately 16.5 grams. Thetemperature control apparatus 100 was sealed in an air-tight containerimmediately after fabrication.

[0083] The temperature control apparatus 100 was tested on a volunteerwith a temperature probe placed between the temperature controlapparatus 100 and the volunteer's skin to measure the temperature. Theresults of this temperature experiment is illustrated in FIG. 5 andTable A, which shows that the temperature control apparatus 100 iscapable of keeping the skin temperature to a narrow, elevated range ofabout 41° C. to 43° C. for extended period of time (at least about 240minutes). TABLE A Time (minutes) Temperature (° C.) 0 30.6 1 31.8 2 33.63 35.2 4 36.6 5 38.0 6 39.1 7 39.9 8 40.5 9 41.1 10 41.5 11 41.9 12 42.313 42.5 14 42.5 15 42.5 16 42.5 17 42.5 18 42.5 19 42.5 20 42.5 22 42.424 42.4 26 42.3 28 42.2 30 42.5 35 42.5 40 42.6 45 42.6 60 42.5 75 42.890 42.7 120 42.6 150 42.3 180 42.0 210 41.8 240 41.0 255 40.4

[0084] Nine human volunteers receive a dose of fentanyl in a DDDS 120.The DDDS 120 comprised a commercially available dermal fentanyl patch,Duragesic-50® (designed to deliver an average of 50 micrograms offentanyl per hour), distributed by Jansen Pharmaceutica, Inc. ofPiscataway, N.J., USA. The experiment was conducted to determinefentanyl concentrations within the volunteers' blood (over a 12 hourperiod) without heating DDDS 120 and with heating the DDDS 120 (with thetepmerature control apparatus 100 described above). The experiments wereconducted with at least a two week time period between the heated andunheated sessions. In the unheated session, the DDDS 120 was appliedonto the volunteer's chest skin and removed after about 240 minutes. Inthe heated session, the DDDS 120 was applied onto the subject's chestskin and immediately cover by the temperature control apparatus 100.Both the DDDS 120 and the temperature control apparatus 100 were removedafter about 240 minutes. In both sessions, blood samples were taken atvarious intervals for 12 hours and the fentanyl concentrations in serumsamples were determined by radioimmunoassay.

[0085]FIG. 6 and Table B illustrates the mean serum fentanylconcentrations produced by the heated and unheated Duragesic-50®patches, respectively, over a 720 minute duration (The lowest standardused in the assay was 0.11 ng/ml. Concentrations lower than 0.11 ng/mlwere obtained using an extrapolation method.). With heating by thetemperature control apparatus 100, it was found that fentanyl began toenter the systemic circulation earlier, and at faster rates. At 240minutes, the end of the heating and fentanyl patch application, theaverage serum concentrations of fentanyl in the volunteers with theheating of the Duragesic-50® patch was about 5 times that of theunheated Duragesic-50®. These results demonstrates that controlled heatcan significantly increase the speed of dermal fentanyl absorption andshorten the onset time. TABLE B Serum Fentanyl Conc. Serum FentanylConc. Without Heat With Heat Time (minutes) (ng/ml) (ng/ml) 0 0.04 0.0110 0.03 0.01 20 0.03 0.02 30 0.03 0.03 40 0.03 0.06 60 0.04 0.09 75 0.030.16 90 0.04 0.28 120 0.06 0.45 180 0.14 0.85 240 0.26 1.29 300 0.471.04 360 0.40 0.98 420 0.33 0.88 480 0.35 0.67 540 0.38 0.63 600 0.370.51 660 0.33 0.50 720 0.26 0.49

[0086] Thus, it is believed that the increased temperature increases theskin permeability (compared with a DDDS without such a heatingmechanism), which results in the fentanyl entering the patient'ssystemic circulation faster. This should result in serum fentanylconcentrations reaching steady state quicker. The heating is alsobelieved to increase the body fluid circulation and blood vessel wallpermeability in the sub-skin tissues, and cause fentanyl to spend lesstime in the sub-skin depot site. As a result, the patient receives theanalgesic compound more quickly and receives improved pain relief.

[0087] In yet another experiment, the temperature control apparatus 100comprised the side walls 106 defined by a {fraction (3/16)} inch thickrectangular foam tape (3 layers of No. 1779 {fraction (1/16)}″ whitefoam tape, 3M Corporation, Minneapolis, Minn., USA) with an outerdimension of about 2.25 inches by 4 inches with an opening thereinhaving an inner dimension of about 1.75 inches by 3.5 inches, the bottomwall 102 comprising rectangular medical tape (No. 1525L plastic medicaltape, 3M Corporation, Minneapolis, Minn., USA) of a dimension of about2.25 inches by 4 inches with a non-adhesive side attached to the bottomof the side walls 106, and a top wall 104 comprising a rectangular{fraction (1/32)} inch thick foam tape (No. 9773 {fraction (1/32)}″ tanfoam tape, 3M Corporation, Minneapolis, Minn., USA) with seventy-eightholes 114 therethrough (diameters approximately {fraction (1/32)} inch,in a 6 by 13 pattern with about a 6 mm center spacing). The side walls106, the bottom wall 102, and the top wall 104 define a chamber. Theholes 114 of the top wall 104 are covered by an air permeable membrane116 comprising a porous membrane (No. 9711 CoTran™ membrane, 3MCorporation, Minneapolis, Minn., USA) disposed between the top wall 104and the temperature regulating mechanism 108. The side walls 106, thebottom wall 102, and the top wall 104 all had ⅛″ rounded corners. Thetemperature regulating mechanism 108 disposed in the chamber comprised amixture of activated carbon, iron powder, saw dust, sodium chloride andwater in the weight ratio of approximately 5:16:3:2:6 weighingapproximately 25 grams. This temperature control apparatus 100 wastested on a volunteer's stomach with a temperature probe placed betweenthe temperature control apparatus 100 and the volunteer's skin tomeasure the temperature. The results of this temperature experiment isillustrated in FIG. 7 and Table C, which shows that the temperaturecontrol apparatus 100 is capable of keeping the skin temperature to anarrow, elevated range at between about 41 and 44° C. for extendedperiod of time (at least about 450 minutes). TABLE C Time (minutes)Temperature (° C.) 0 29.6 1 31.9 15 39.3 16 39.9 17 40.6 18 41.0 19 41.420 41.9 22 42.7 24 43.2 26 43.6 28 43.7 30 43.5 35 43.5 40 43.3 45 43.360 43.1 75 42.9 90 43.0 120 43.0 150 43.2 180 43.0 210 42.6 240 42.5 27042.3 300 43.0 330 43.0 360 42.6 390 42.6 420 42.5 450 41.9

[0088]FIG. 8 illustrates another embodiment of a temperature controlapparatus 150 comprising a temperature regulating mechanism 108surrounded by a bottom wall 102, a top wall 104, and side walls 152. Theside walls 152 extend a distance below the bottom wall 102 to define acavity 154. The bottom wall 102 is preferably made of plastic tapematerial and the side walls 152 are preferably made of a flexiblenon-air permeable material, such as non-air permeable closed-cell foammaterial. A portion of the bottom of the temperature control apparatus150 includes an adhesive material 112 on the bottom of the side walls152 and, preferably, includes a second adhesive material 156 in thebottom of the bottom wall 102, wherein the second adhesive material 156is preferably less adhesive than the adhesive material 112. Again, thetemperature regulating mechanism 108 preferably comprises a compositionof activated carbon, iron powder, sodium chloride, water, and,optionally, saw dust. The top wall 104 is preferably also a flexiblenon-air permeable material having holes 114 therethrough. An airpermeable membrane 116 is disposed between the top wall 104 and thetemperature regulating mechanism 108 to regulate the amount of airreaching the temperature regulating mechanism 108 through the holes 114.

[0089]FIG. 9 illustrates a DDDS 160 comprising a housing made 122 ifflexible materials. The housing 122 preferably comprises side walls 124and a top wall 126 with a drug formulation 128 disposed within thehousing 122, and may include a membrane 130 which may be a rate-limitingmembrane.

[0090]FIG. 10 illustrates the temperature control apparatus 150 of FIG.8 attached to the DDDS 160 of FIG. 9. The DDDS 160 is placed on (orattached with an adhesive, not shown) a portion of the skin 134 of apatient and the temperature control apparatus 150 is placed over theDDDS 160, such that the DDDS 160 resides within the cavity 154 (see FIG.8). The adhesive material 112 attaches to the skin 134 and holds thetemperature control apparatus 150 in place. If the DDDS 160 is notattached to the skin 134, the temperature control apparatus 150 holdsthe DDDS 160 in place. Preferably, the DDDS 160 is attached to the skin134 with an adhesive material (not shown) with the temperature controlapparatus 150 placed over the DDDS 160. The temperature controlapparatus 150 is attached to the skin 134 with the adhesive material 112and the second adhesive material 156 (less adhesive than any attachmentadhesive (not shown) between the DDDS 160 and the skin 134 and lessadhesive than the adhesive material 112 between the temperature controlapparatus 150 and the skin 134) attaches the temperature controlapparatus 150 to the DDDS 160. Such an arrangement results in secureadhesion of the temperature control apparatus 150 and the DDDS 160 tothe skin 134, yet allows for the removal of the temperature controlapparatus 150 without removing the DDDS 160.

[0091]FIG. 11 illustrates an alternate DDDS 165 comprising a housing 123made of flexible material(s). The housing 123 preferably comprises topwall 125 and a membrane 103, which may be a rate-limiting membrane, witha drug formulation 128 disposed within the housing 123. FIG. 12illustrates the temperature control apparatus 150 of FIG. 8 attached tothe DDDS 165 of FIG. 11, similar that described for FIG. 10.

EXAMPLE 2

[0092] An example of using the embodiment of the present inventionillustrated in FIGS. 8-12 for administering analgesic material to treatbreakthrough pain consists of a patient or care giver placing the DDDS160, 165 on the skin 134 of the patient with the temperature controlapparatus 150 placed thereover. By way of example, when the DDDS 160,165 is a commercially available fentanyl patch, Duragesic-50®, it takesseveral hours after the application of the DDDS 160, 165 to obtain asufficient steady state level of fentanyl in the patient's bloodstreamto control baseline pain. However, such as with the treatment of cancerpatients, a patient will from time to time suffer breakthrough pain,which is a suddenly increased but usually not long lasting pain. When apatient feels that a breakthrough pain episode is imminent, the patientplaces the temperature control apparatus 150 over the DDDS 160, 165. Theheat from the temperature control apparatus 150 increases thetemperature of the fentanyl patch, the skin, and tissues under the skin.As a result, more fentanyl is absorbed across the skin. Furthermore,fentanyl already in the skin and sub-skin depot sites (i.e., fentanylmolecules that have already permeated across the skin but were stored inthe skin and sub-skin tissues) starts to be released into the systemiccirculation at faster rates because of increased blood/body fluid flowin the tissues under the fentanyl patch and increment blood vessel wallpermeability caused by heat from the temperature control apparatus 150.The overall result is that fentanyl concentration in the patient'sbloodstream is significantly increased shortly after the heating patchis applied (compared with no temperature control apparatus 150 beingused), and the increased fentanyl in the bloodstream alleviates thebreakthrough pain in a timely manner. It is believed that for lipophiliccompounds, such as fentanyl, that usually have significant dermal depoteffect (storage in depot sites in the skin and sub-skin tissues andgradual release from the depot sites), the increased drug release fromthe depot sites due to the heating may make a more rapid and a moresignificant contribution to increasing bloodstream drug concentrationsthan the contribution from increased skin permeability caused by theheat. The patient can leave the heating patch on for a pre-determinedlength of time, based on his previous experience of breakthrough pain,before he stops the heating by removing the patch or placing an airimpermeable tape to cover all the holes on the top wall 104. The patientmay also stop the heating when he feels the current episode ofbreakthrough pain is over or beginning to end.

[0093] Preferably, the heating patch is designed to have a predeterminedheating duration that is sufficient to treat most patients' breakthroughpain, but not long enough to cause serious side effects associated withfentanyl overdose. However, if a particular patient has a highertolerance to fentanyl, the patient can use two or more of the heatingpatches consecutively so that the patient gets just enough extrafentanyl to treat the breakthrough pain.

EXAMPLE 3

[0094] Another example of using the embodiment of the present inventionillustrated in FIGS. 8-12 for dermally administering nicotine forsuppressing nicotine craving consists of a user placing a nicotine DDDS160, 165 on the skin 134. After a few hours, the user should obtain asteady state nicotine concentration in the bloodstream that issufficient to suppress a “baseline” nicotine craving. When the userstarts to have an episode of increased nicotine craving, the user putsthe temperature control apparatus 150 on top of the DDDS 160, 165. Thetemperature control apparatus 150 preferably heats for at least 15minutes before the exothermic reaction exhausts the temperatureregulating mechanism 108. The heat increases the transport of nicotineacross the skin, and increases the blood flow in the tissues under theDDDS 160, 165 which carries nicotine stored in the tissues under theDDDS 160, 165 into the systemic circulation at increased rates. As aresult, the user gets a rapid increase in his blood nicotineconcentration to treat the surge of the nicotine craving. After theheating, the nicotine absorption rates gradually come back to normal todeliver the steady state nicotine concentration in the bloodstream.

EXAMPLE 4

[0095] Another example of using the embodiment of the present inventionillustrated in FIGS. 8-12 for dermally administering testosterone toincrease and optimize the amount of drug delivered consists of a userplacing the DDDS 160, 165, such as a once a day dermal testosteronepatch, for example Androderm® produced by Theratech, Inc. of Salt LakeCity, Utah, USA, on the skin 134. The DDDS 160, 165 is generally appliedto the skin 134 at night, for example at 10 PM. However, if the userdoes not get a sufficient dosage of testosterone the next day, the userputs the temperature control apparatus 150 on top of the DDDS 160, 165.The increased temperature in the DDDS 160, 165, the skin 134 and tissuesunder the skin significantly increase the dermal absorption oftestosterone. In addition, if the DDDS 160, 165 has permeation enhancer,such as glycerol monooleate, the heat should also make the enhancerpermeate the skin faster, thus making it more effective. The ultimateresult is that the user gets sufficient testosterone from the DDDS 160,165. Furthermore, the user may also place the temperature controlapparatus 150 on the DDDS 160, 165 in the morning to deliver moretestosterone from morning to the evening when the user needs the higherdosage the most. The increased absorption of testosterone by thecontrolled heating may allow the readuction of a permeation enhancerconcentration which is used in the DDDS 160, 165. In a testosteroneDDDS, a permeation enhancer is usually necessary for deliveringsufficient testosterone, however permeation enhancers may cause seriousskin irritation, such as glycerol monooleate in Androderm®.

EXAMPLE 5

[0096] It is, of course, understood that the DDDS 160, 165 and thetemperature control apparatus 150 can be with athletic injuries. Forexample, if a person injures an elbow in a sporting event or such, theuser can apply a DDDS 160, 165 containing an analgesic, such adexamethasone, wintergreen oil, or the like, wherein the DDDS 160, 165.The heat generated by the temperature control apparatus 150 drives moredrug into the elbow and the increased the blood flow induced by the heattakes the drug deeper into the elbow.

EXAMPLE 6

[0097] Yet another example of using the embodiment of the presentinvention illustrated in FIGS. 8-12 comprises using the temperaturecontrol apparatus 150 for administering analgesic material to treat painwhen the diffusion coefficient of the active ingredients in theformulation 128 and/or permeability coefficient across a rate limitingmembrane 130 is so low that it dominantly determines the overallabsorption rate of analgesic material from the DDDS 160, 165 into apatient's body. By way of example with the use of a DDDS 160, 165, thepatient or care giver places the DDDS 160, 165 on the skin 134 of thepatient. If after a time of wearing the DDDS 160, 165, it is determinedthat for this particular patient and his conditions a higherconcentration of fentanyl in the bloodstream is required to properlytreat his pain, the temperature control apparatus 150 is placed on topof the DDDS 160, 165 to heat the DDDS 160, 165.

[0098] The increased temperature increases diffusion coefficient of theactive ingredient in the formulation in the DDDS 160, 165 and increasesthe permeability coefficient across the rate limit membrane 130 in theDDDS 160, 165, and, thus, the overall rates at which the activeingredient enters the patient's body. This, in turn, increases theconcentration of active ingredient in the bloodstream. As a result, thepatient gets the increased and proper effect.

EXAMPLE 7

[0099] Still another example of using the embodiment of the presentinvention illustrated in FIGS. 8-12 comprises using the temperaturecontrol apparatus 150 for decreasing onset time of an analgesic materialfrom the DDDS 160, 165. By way of example with the use of a commerciallyavailable fentanyl patch, such as Duragesic-50®, as the DDDS 160, 165,the patient or care giver places the DDDS 160, 165 on the skin 134 ofthe patient and places the temperature control apparatus 150 over theDDDS 160. Preferably, the temperature control apparatus 150 includes asufficient amount of activated carbon, iron powder, sodium chloride, andwater in the temperature regulating mechanism 108 to sustain anexothermic reaction for at least 4 hours.

[0100] The heat from the temperature control apparatus 150 increases thetemperature at a contact surface of the skin 134 and the DDDS 160, 165to temperatures up to about 60° C., preferably a narrow temperaturerange between about 36° C. and 46° C., most preferably between 37° C.and 44° C., and maintains this temperature for a period of time (i.e.,approximately 4 hours). During this time, the heat increases the speedof fentanyl release from the DDDS 160, 165, the permeation rate acrossthe skin 134, and the speed of blood circulation which carriers thefentanyl into the systemic circulation faster. After the exothermicreaction ceases (approximately 4 hours), the fentanyl absorption andconcentration in the bloodstream begins to decrease from the elevatedlevels caused by the heat from the DDDS 160, 165 returns to normal(unheated) levels. The patient continues to wear the system for a totalof between about 48 and 72 hours. Compared with a DDDS 160, 165 withoutthe use of the temperature control apparatus 150, the fentanyl begins toappear in the bloodstream significantly earlier to yield a shortenedonset time and the fentanyl concentrations in the bloodstream in theearly hours of application are significantly higher than that producedby an unheated DDDS 160, 165. The therapeutic serum fentanylconcentration varies from person to person. For example some peoplerespond to levels above 0.2 ng/mL. Referring to FIG. 6, this 0.2 ng/mLconcentration is achieved in about one-third the amount of time for aheated system than for a non-heated system (i.e., about 70 minutes ascompared with about 210 minutes).

[0101] After a period of time when the exothermic reaction oftemperature control apparatus 150 slowly stops generating heat, thefentanyl concentration in the bloodstream starts to gradually approachthe normal steady state fentanyl concentrations in the bloodstream whichwould ultimately be seen with an unheated DDDS 160, 165, given asufficient amount of time. As a result, the temperature controlapparatus 150 significantly shortens the onset time of Duragesic-50 ®without significantly altering its steady state delivery rates. Thus,the important advantage provided by this approach is that the onset timeof a DDDS 160, 165 already in cinical use can be shortened withoutsignificantly altering its steady state delivery rates which are notonly adequate, but also familiar to the caregivers and the patients.

EXAMPLE 8

[0102] A further example of using the embodiment of the presentinvention illustrated in FIGS. 8-12 comprises using the temperaturecontrol apparatus 150 for a sustained high absorption rate of ananalgesic material from the DDDS 160, 165. Cancer patient's tend todevelop a tolerance for fentanyl (and other analgesic materials) afterextended use. For example, if a patient becomes tolerant to aDuragesic-100® (100 micrograms/hour deliver rate) dermal patch, a caregiver may apply both a Duragesic-100® and a Duragesic-50® (50micrograms/hour delivery rate) to treat the patient's cancer pain.However, instead of using two Duragesic® patches, a care giver can use aDuragesic-75® (75 micrograms/hour delivery rate) patch in conjunctionwith the temperature control apparatus 150, preferably designed to lastbetween about 12 and 24 hours, to increase the fentanyl absorption. Thecare giver replaces the heating patch, after the designed heating duringis over, with another heating patch to maintain a desired temperature,and continues to do so until the fentanyl in the Duragesic-75® patch canno longer supply a therapeutic amount of fentanyl. It is, of course,understood that the temperature control apparatus 150 may be designed tolast as long as the expected usage time of the Duragesic-75® dermalpatch.

[0103] Heating patches with different heating temperatures may be usedto achieve different increased levels of fentanyl deliver rates.

EXAMPLE 9

[0104] Yet still another example of using the embodiment of the presentinvention illustrated in FIGS. 8-12 again comprises using thetemperature control apparatus 150 for decreasing onset time of ananalgesic material from the DDDS 160, 165. By way of example, a localanaesthetic, such as a eutectic mixture of lidocaine and tetracaine, canbe administer with a DDDS 160, 165 to numb the skin 134 before a painfulmedical procedure. A faster onset and deeper numbing effect within ashort time can be achieved by placing the temperature control apparatus150 over the DDDS 160, 165, wherein the temperature control apparatus150 is capable of providing heating the skin to a narrow range betweenabout 37° C. and 41° C., preferably between 39° C. and 40° C., for atleast 30 minutes. The skin 134 should be numb in 30 minute or less,which is much shorter than that without heating. Depending on theoriginal skin temperature, it is believed that such heating will reducethe onset time by about 60% of the onset time without heating.

EXAMPLE 10

[0105] Still another example of using the embodiment of the presentinvention illustrated in FIGS. 8-12 again comprises using thetemperature control apparatus 150 for increasing the solubility of ananalgesic from the DDDS 160, 165. By way of example, a formulation maybe designed to contain an analgesic which has such low solubility in theformulation that a significant portion is in the form of undissolvedparitcles, and the solubility increases with increasing the temperatureof the formulation.

[0106] A patient places such a DDDS 160, 165 on his skin. If the amountof the analgesic compound the patient receives from the DDDS 160, 165 isnot sufficient, the patient places the temperature control apparatus 150on or over the DDDS 160, 165. The heat generated in the temperaturecontrol apparatus 150 increases the temperature of the formulation inthe DDDS 160, 165 and maintains the increased temperature for asignificant part or substantially the entire length of the DDDS 160, 165application. The increased temperature in the formulation increases thesolubility of the analgesic compound in the formulation. Consequently,more analgesic compounds are dissolved in the formulation which giveshigher driving force for the transdermal permeation of the analgesiccompound. As a result, more of the analgesic compound enters thepatient's body.

[0107] Another variation of this example is for the treatment ofbreakthrough pain. If the solubility of the analgesic compound in aformulation in the DDDS 160, 165 is sufficient to treat baseline pain,but not breakthrough pain, a patient can place the temperature controlapparatus 150 on or over the DDDS 160, 165 when an episode ofbreakthrough pain occurs. The increased solubility of the analgesiccompound in the formulation results in the patient obtaining moreanalgesic compound to treat the breakthrough pain. The heating from thetemperature control apparatus can be discontinued after the patientdetermines that the pain is under control.

[0108] Although Examples 1-10 discuss the application of specific drugs,it is, of course, understood that the present invention is not limitedto any particular drug(s). It is understood that a considerable varietyof drugs classes and specific drugs may be used with the presentinvention. The drug classes can include without limitation androgen,estrogen, non-steroidal anti-inflammatory agents, anti-hypertensiveagents, analgesic agents, anti-depressants, antibiotics, anti-canceragents, local anesthetics, antiemetics, anti-infectants, contraceptives,anti-diabetic agents, steroids, anti-allergy agents, anti-migraineagents, agents for smoking cessation, and anti-obesity agents. Specificdrugs can include without limitation nicotine, testosterone, estradiol,nitroglycerin, clonidine, dexamethasone, wintergreen oil, tetracaine,lidocaine, fentanyl, sufentanil, progestrone, insulin, Vitamin A,Vitamin C, Vitamin E, prilocaine, bupivacaine, sumatriptan, anddihydroergotamine.

EXAMPLE 11

[0109] Yet still another example of using the embodiment of the presentinvention illustrated in FIGS. 8-12 again comprises using thetemperature control apparatus 150 for maintaining a stable temperaturefor the DDDS 160, 165. Certain drugs have relatively low therapeuticindices, meaning that the differences between the therapeutic dose andthe dose which can cause serious and/or undesired side effects aresmall. Thus, dermal delivery of such drugs can be dangerous (over-dose)or ineffective (under-dose), especially for individuals whose skin areexposed to highly variable ambient temperatures, such as people workingoutdoors in extreme weather conditions. The variations in ambienttemperature can cause variations in skin temperature which cansignificantly change the ultimate dermal absorption of the drugs.Covering a DDDS 160, 165 containing a low therapeutic indices drug withthe temperature control apparatus 150 can regulate the skin temperatureto a narrower range and reduce the variation in dermal drug absorption.Drugs and classes of drugs that may benefit from this method include,but are not limited to, drugs such as nicotine, nitroglycerin,clonidine, fentanyl, sufentanil, and insulin; and classes of drugs suchas non-steroidal anti-inflammatory agents, anti-hypertensive agents,analgesic agents, anti-diabetic agents, and anti-migraine agents.

[0110] FIGS. 13-19 illustrates another embodiment of a temperaturecontrol apparatus 170. FIG. 13 illustrates the temperature controlapparatus 170 which is similar to the embodiment of FIG. 8, butcomprises a temperature regulating mechanism 108 which is made up of aplurality of chambers 172 separated by non-air permeable walls 174. Thetemperature regulating mechanism 108 is substantially surrounded by abottom wall 102, a top wall 104, and side walls 152. Again, thetemperature regulating mechanism 108 preferably comprises a compositionof activated carbon, iron powder, sodium chloride, water, and,optionally, saw dust, which is disposed in each of the chambers 172. Thetop wall 104 is preferably also a flexible non-air permeable materialhaving a plurality of holes 114 therethrough, preferably, a row of holes114 for each chamber 172. An air permeable membrane 116 is disposedbetween the top wall 104 and the temperature regulating mechanism 108 toregulate the amount of air reaching the temperature regulating mechanism108 through the holes 114. The top wall 104 can have at least one covercovering the plurality of holes 114 for the regulation of the air intothe chambers 172. As illustrated in FIG. 13, three covers are layered onthe top wall 104. A first cover layer 176 is affixed to the top wall 104and has openings 178 (see FIG. 17) to expose 2 out of 3 holes 114. Asecond cover layer 182 is affixed to the first cover layer 176 and hasopening 184 (see FIG. 15) to expose 1 out of 3 holes 114. A top cover186, which has no openings, is affixed to the second cover layer 182.Thus, a patient has a various opinions on what percentage of chambers172 to expose to ambient air. If the heat generated from one third ofthe chambers is required, the top cover 186 is removed, as shown inFIGS. 14 and 15. If the heat generated from two thirds of the chambersis required or if another additional heat is needed after the depletionof the first one-third of the temperature regulating mechanism 108, thetop cover 186 and the second cover layer are removed, as shown in FIGS.16 and 17. If the heat generated from all of the chambers is required orif another additional heat is needed after the depletion of the firstand second one-third of the temperature regulating mechanism 108, thetop cover 186, the second cover layer 182, and the first cover layer 176are removed, as shown in FIGS. 18 and 19. It is, of course, understoodthat more or less cover layers can be used with any number of holes toresults in any desired amounts of the temperature regulating mechanism108 being activated.

[0111] Thus, by way of example a patient can have a number of choices inusing the temperature control apparatus 170, such for the suppression ofbreakthrough pain. When the breakthrough pain occurs, the patent placesthe temperature control apparatus 170 over an analgesic material DDDSand can do any of the following:

[0112] 1) Activate a particular number or percent of chambers 172 byremoving the requisite covers depending on how much additional analgesicmaterial is required to treat the breakthrough pain. The covers can bepreferably replaced to stop the exothermic reaction when no moreadditional analgesic material is required.

[0113] 2) Activate a particular number or percent of chambers 172,exhaust the heat generating capacity of those chambers 172, and thenactivate other (non-activated) chambers 172. This extends the heatingduration of the temperature control apparatus 170. The duration of thetotal heating time is determined by the typical duration of theparticular patient's breakthrough pain.

[0114] 3) Activate enough chambers 172 to treat one episode ofbreakthrough pain, and leave the heating patch in place. When the nextepisode of breakthrough pain occurs, activate unused chambers 172.

[0115]FIG. 20 illustrates a dermal drug delivery system 190 (hereinafter“DDDS 190”) having a rate limiting membrane 192. The structure of DDDS190 is similar to that of FIG. 3. However, the DDDS 190 includes a ratelimiting membrane 192 which resides between the drug formulation 128 andthe skin 134 of a patient.

[0116] Generally, the permeability of the drug in the drug formulation128 through the rate limiting member 192 is significantly lower than thepermeability of the drug in the drug formulation 128 into the skin of anaverage patient. Rate limiting membranes 192 are used to minimize thevariation in overall permeation, and to regulate the amount of drugdelivered to the patient so that overdosing does not occur. Anotheraspect of the present invention is the use of a temperature sensitiverate limiting membrane, such that the drug permeation rate through therate limiting membrane increases significantly with increasingtemperature. With such a DDDS 190, the above discussed temperaturecontrol mechanisms 100 (FIG. 1 & 2), 150 (FIG. 8), and 170 (FIG. 13) canbe used to increase the drug delivery rate across the rate limitingmembrane 192 to treat breakthrough pain, reduce onset time, increasesteady state delivery rate, or other advantages discussed above.

[0117] The possible temperature control mechanisms are not limited tothe exothermic reaction mixture of iron powder, activated carbon, salt,water, and sawdust, as discussed above. FIG. 21 illustrates an electrictemperature control mechanism 200 comprising an electric heating element202 surrounded by a bottom wall 102, a top wall 104, and side walls 152(similar to FIG. 8). The side walls 152, preferably, extend a distancebelow the bottom wall 102 to define a cavity 154. It is, of course,understood that the electric heating element 202 does not have to havethe side walls 152 forming a cavity 154.

[0118] The bottom wall 102 and the side walls 152 are preferably made ofa flexible non-air permeable material, such as non-air permeableclosed-cell foam material. A portion of the bottom of the temperaturecontrol apparatus 200 includes an adhesive material 112 on the bottom ofthe side walls 152 and, preferably, includes a second adhesive material156 in the bottom of the bottom wall 102, wherein the second adhesivematerial 156 is preferably less adhesive than the adhesive material 112.The electric heating element 202 preferably comprises a flexibleresistor plate that can generate heat when supplied with an electriccurrent through traces 206, 208. The electric current is preferablysupplied from a battery 212 attached to a control mechanism 214, and anelectronic switch 216. The battery 212, the control mechanism 214, andthe electronic switch 216 are preferably attached to the top surface ofthe top wall 104. The electric heating element 202 is activated bytriggering the electronic switch 216 which begins the flow of electriccurrent from the battery 212 to the electric heating element 202. Atemperature sensor 218, such as a thermistor, is preferably attached tothe bottom of the bottom wall 102 and sends a signal (corresponding tothe temperature at the bottom of the bottom wall 102) through electrictrace 222 to the control mechanism 214. The control mechanism 214regulates the flow of current to the electric heating element 202, sothat the electric heating element 202 quickly brings the temperature ata contact surface between the bottom wall 102 and a top of a DDDS (notshown) to a pre-determined level and maintains the temperature at thatpre-determined level. The following features may be incorporated intothe control mechanism 214: 1) a mechanism that allows a physician orcare giver set the length of each heating period for each patient, whichallows the physician to limit the heating, and hence the extra drug thatthe patient can get based on the conditions of the patient; 2) amechanism that allows the physician or care giver to set the minimumtime between the heating periods, and hence how often the patient canget the extra drug through increase heat; 3) a mechanism that allows thephysician or care giver to set a pre-determined temperature; and/or 4) amechanism that allows the physician or care giver to control the heatingtemperature profile, such as gradually increasing heating temperature ordecreasing temperature over a pre-determined period of time. Thesefeatures can potentially give simple DDDSs a variety of control optionsfor the physician and/or the patient on the qunantity and timing of thedelivery of extra drug.

EXAMPLE 12

[0119] An example of using the embodiment of the present invention, suchas illustrated in FIG. 21, includes using the temperature controlmechanism 200 for decreasing onset time of a local anesthetic comprisingapproximately 14% tetracaine/lidocaine eutectic mixture by weight; 8.6%polyvinyl alcohol (PVA) by weight, 0. 17% sodium hydroxide (NaOH) byweight, and the remainder water (H₂O). The local anesthetic, in the formof a thin patch, was placed on a volunteer's left forearm and thetemperature control mechanism 200, set to maintain a 41° C. temperature,was placed over the local anesthetic. The local anesthetic was alsoplaced on a volunteer's right forearm (at a different time) and left atroom temperature (about 24° C.). The results are presented in Table D,wherein the effect of the local anesthetic was measure by a pain scorewhen the skin is poked by a blunt object. The pain score is defined asfollows: TABLE D Score Effect 0 No effect 1 Between no numbness andmedium numb 2 Medium numb 3 almost completely numb 4 completely numb,but not deep 5 completely numb and deep Time (minutes) Pain Score withHeating Pain Score w/o Heating 15 4 2 20 5 3 25 4 30 5

[0120] Thus, it can be seen that heating reduced the onset time ofcomplete and deep numbness by approximately 33%.

EXAMPLE 13

[0121] Another example of using the embodiment of the present invention,such as illustrated in FIG. 21, includes using the temperature controlmechanism 200 for a sustained high absorption rate of an analgesicmaterial from the DDDS 160, 165. Cancer patient's tend to develop atolerance for fentanyl (and other analgesic materials) after extendeduse. For example, if a cancer patient becomes tolerant to aDuragesic-100® (100 micrograms/hour deliver rate) dermal patch, a caregiver may apply an electric heating device, such as temperature controlmechanism 200, on a Duragesic-100® patch and sets the temperature toheat the skin surface to 38° C. to obtain a higher rate of fentanyldelivery from the Duragesic-100® patch for treating the patient's cancerpain. However, if, after a duration of treatment, the cancer patientbecomes tolerant the fentanyl delivery rate at 38° C., the care givercan adjust the temperature control mechanism 200 on the ofDuragesic-100® patch to heat the skin surface to 40° C. to obtain aneven higher rate of fentanyl delivery from the Duragesic-100® patch fortreating the patient's cancer pain.

[0122]FIG. 22 illustrates another embodiment of a temperature controlapparatus 240 comprising a substantially flat, flexible bag 242 filledwith a supercooled liquid 244, such as a concentrated solution of sodiumacetate. A bottom portion of the bag 242, preferably, includes anadhesive material 246. The bag 242 is preferably slightly larger thanthe DDDS 160 such that the adhesive material 246 may contact and adhereto the skin 134. The bag 242 further includes a triggering mechanism248, such as a metal strip. For example, when a patient wearing a DDDScontaining an appropriate analgesic material feels the imminent onset ofbreakthrough pain, the bag 242 is placed over the DDDS 160. Thetriggering mechanism 248 is activated (such as by bending a metal strip)which triggers crystallization in the supercooled liquid. The heatgenerated by the crystallization (phase transition) increases the speedof transport of analgesic material into the body and the speeds therelease of analgesic material from the depot sites in the skin and thesub-skin tissues. As a result the patient gets a rapid delivery of extraanalgesic material to treat breakthrough pain. Usually, the heatgenerated by a phase transition can not be sustained over extended time,but may be enough to release adequate amount of analgesic material fromthe depot sites in the tissues under the skin to treat the breakthroughpain. The advantage of the temperature control apparatus 240 is that itis reusable. After use, the temperature control apparatus 240 can beplaced in hot water and then cooled to room temperature to transfer thesolidified contents in the bag back to a supercooled liquid 244.

EXAMPLE 14

[0123] An example of using the embodiment of the present inventionillustrated in FIGS. 23-24 comprises using a temperature controlapparatus 300 which is capable of heating and cooling, such that therate of absorption of a drug formulation in a DDDS can be increased ordecreased, as needed.

[0124] For example, as shown in FIG. 23, if the level of the drug in thepatient's system requires adjusting, the temperature control apparatus300 is placed on a DDDS 160. Heating will result in an increase in drugabsorption (as previously discussed) and cooling will reduce drugabsorption to prevent overdose. FIG. 23 illustrates the temperaturecontrol apparatus 300 as a thermoelectric module which is be used forboth heating or cooling. The temperature control apparatus 300 functionsas a small heat pump, wherein a low voltage DC power source 304 providesa current in one direction 306 to a thermoelectric unit 310 whichresults in heating on a first side 308 (preferably a ceramic substrace)of the temperature control apparatus 300 and cooling on a second side312 (preferably a finned dissipation structure) of the temperaturecontrol apparatus 300. If the current direction is reversed, the firstside 308 will cool and the second side will heat.

[0125] The temperature control apparatus 300 may be control with aclosed loop temperature controller 314, as shown in FIG. 24. Thetemperature controller 314 comprises a positive DC node 316 and anegative DC node 318 supplying circuit to a primary circuit 320. Theprimary circuit 320 delivers an electrical signal 322 through a voltageamplifier 324 and a power amplifier 326 to the thermoelectric unit 310.The primary circuit 320 further includes a temperature sensor 328receiving a temperature signal 330 from the thermoelectric unit 310, andfurther includes a temperature adjustment mechanism 332, which adjuststhe electrical signal 322.

[0126] A variety of drugs and drug classes can be utilized with suchtreatments. The drugs include, but are not limited to, nicotine,nitroglycerin, clonidine, dexamethasone, fentanyl, sufentanil, andinsulin. The drug classes include, but are not limited to, androgen,non-steroidal anti-inflammatory agents, anti-hypertensive agents,analgesic agents, anti-depressants, anti-cancer agents, anti-diabeticagents, steroids, anti-migraine agents, anti-asthma agents, and agentsfor smoking cessation.

[0127] It is, of course, understood that the heating devices discussedabove could be replaced by an infrared heating device with a feedbackmechanism. All of the controls and variations in controls discussedabove would apply to such an infrared heating device. The advantage ofinfrared radiation over simple heat is that the former, with properwavelengths, penetrates deeper into a patient's skin.

[0128] Another aspect of the present invention is to use heat and otherphysical means, such as ultrasound, microwave, electric current, andvibration, to improve absorption of drugs from depot/storage sites. Suchdepot/storage sites may exist as a result of a drug administered from adermal patch or a drug directly injected or implanted under the skinsurface.

[0129] The kind of formulations that may respond to the physicalinducing means discussed above are: Ultrasound: particles containingdrug formulation that can break down in size when treated withultrasound. Microwave: drugs that have limited solubility in surroundingbody fluid, but the solubility increases significantly with increasingtemperature; and solid formulations whose erosion/degrada- tion speedcan be significantly increased by increasing flow/ exchange of bodyfluid surrounding it. Electricity: drugs that exist in ionized form inthe formulations and/or surrounding body fluid. Vibration: drugs thathave limited solubility in body fluid; solid formulations whoseerosion/degradation speed can be signi- ficantly increased by increasingflow/exchange of body flu- id surrounding it.

EXAMPLE 15

[0130] One example of enhanced depot site absorption using theembodiment of the present invention illustrated in FIGS. 1 and 2 foradministering analgesic material for pain relief consists of a patientor care giver placing the DDDS, such as a fentanyl-containing DDDS, onthe skin of the patient at a first location. After sufficient depletionof the drug in the DDDS, the DDDS is removed and a second DDDS is placedon the skin of the patient at a second location to continue drugdelivery. If an episode of breakthrough pain occurs, the temperaturecontrol apparatus 100 can be applied directly to the patient's skin 134at the first location (the DDDS is no longer present), as shown in FIG.25. The heat from the temperature control device 100 increases the speedof drug release from the depot site 252 in the first skin site and thetissues thereunder to give an increased drug absorption into thesystemic circulation 254 to treat the breakthrough pain.

EXAMPLE 16

[0131] An example of storage site absorption using the embodiment of thepresent invention illustrated in FIGS. 1 and 2 consists of a patient orcare giver introducing an extended release insulin into his skin byinjection or other method such as ultrasound speed hitting (such asproducts similar to those developed by Powderject Pharmaceutical, UnitedKingdom). In the extended release insulin formulation, most of theinsulin molecules are in crystalline form. After injection, insulin isreleased from the crystalline from slowly as the crystals slowlydissolve in the surrounding body fluid. This provides a baseline insulinrelease into the systemic circulation. However, the patient needsadditional insulin above the baseline release to suppress sugar frommeals. Thus, before each meal the patient places a temperature controlapparatus 100, preferably designed to control heat for a pre-determinedtime (i.e., between about 15 and 60 minutes), onto the skin over theinjection site where the injected extended release insulin formulationresides. The heat from the temperature control apparatus 100 increasesflow of the blood and another body fluid in the tissues surrounding theextended insulin formulation, which increases the dissolution speed ofthe insulin and carries the insulin into the systemic circulation athigher rate. The heating duration of the temperature control device 100is, preferably, designed to last just long enough to release theadequate amount of extra insulin to deal with the sugar from the meal.Thus, the patient receives proper insulin absorption adjustment from theextended release formulation, and does not have to make a choice betweentaking additional insulin shots before meals or suffer the physiologicalconsequences caused by high blood sugar from the meals.

EXAMPLE 17

[0132] Another example of storage site absorption using the embodimentof the present invention illustrated in FIGS. 1 and 2 consists of apatient or care giver injecting a drug mixed in controlled releaseparticles under the skin surface. By way of example, a controlledrelease formulation of analgesics may comprise an analgesic, is such assufentanil, alfentanil, remifentanil, and morphine, which isincorporated into a controlled release drug delivery system (such asAtrigel™ by Atrix Laboratories, Inc., Fort Collins, Colo., USA)comprising a biodegradable, biocompatible polymer(s) [i.e.,poly(DL-lactide), poly(DL-lactide-co-glycolide),poly(DL-lactide-co-ε-caprolactone), polycaprolactone, or a combinationthereof] in a biodegradable solvent (i.e., N-methyl-2-pyrrolidone). Thecontrolled release formulation is generally injected into a patientwithin 3 cm, preferably within 1 cm, and most preferably 0.3 cm, fromthe skin to control his cancer pain.

[0133] It is understood that any homopolymer or copolymer of lactic andglycolic acid can be utilized. The lactic/glycolic acid polymers aresolids, wherein the drug and polymers are both dissolved in abiodegradable solvent. After the injection, the biodegradable solventdiffuses out leaving behind the polymer(s) in the form of precipitated,biodegradable particles, which holds most of the sufentanil. As thepolymer particles gradually erodes/degrades, the sufentanil is releasedinto the systemic circulation to treat the cancer pain. The release rateof sufentanil is determined by how quickly the polymer particleserodes/degrades in the body.

[0134] The active drug may also be incorporated and delivered into thestorage site using different methods, such as mixing the drug with thebiodegradable, biocompatible polymer(s) in a solvent, evaporating thesolvent to obtain polymer particles mixed with the active drug. The sizeof the drug containing polymer particles should be, small enough to beincorporated (not dissolved) into a suspension in a liquid (preferablyan aqueous liquid). The suspension is injected into the patient's tissueproximate the skin surface. The liquid quickly leaves the depot site,leaving behind a polymer implant containing the active drug. The releaseof active drug from the polymer implant can be increased in the mannerdescribed above.

[0135] Regardless of the implantation method, the normal release rate ofsufentanil is usually sufficient to treat the patients baseline cancerpain, but not enough to treat breakthrough pain. When the patient feelsa breakthrough pain is coming, he places a temperature control apparatus100 over the skin site under which the formulation was injected. Theincreased blood/body fluid flow caused by the heat increases theerosion/degradation speed of the polymer particles and hence the speedof release of sufentanil. When the breakthrough pain is over, thepatient stops the heating (such as by removing the heating patch orcovering the holes 114 on the top wall 104—see FIG. 2) and the polymerparticle erosion/degradation speed gradually returns to normal whichreturns the sufentanil release rate back to a normal, pre-heated rate.

EXAMPLE 18

[0136] The effects of heating on the release of a drug incorporated in abiocompatible, biodegradable polymer matrix were examined. An anesthetic(i.e., lidocaine) was incorporated into the polymer matrix (i.e.,lactide/glycolide polymer) to form an anesthetic drug/polymercomposition. The anesthetic drug/polymer composition may be used forinjecting/planting under the skin of a patient, wherein the drug isgradually released into the body as the polymer matrix slowly erodes inthe body.

[0137] The anesthetic drug/polymer composition was made by dissolvingone tenth of one gram of lactide/glycolide polymer (Medisorb Grade8515DL, Medisorb Technologies International, L. P., Cincinnati, Ohio,USA) and 0.1 gram of lidocaine base in 2 grams of acetone to form asolution. Approximately 5 mL of water (pH adjusted to above 8) wasslowly added into the solution while the solution was stirred by arapidly rotating Teflon coated magnetic bar. A Medisorb-lidocainemixture precipitated out as a textured material attached on the magneticbar and as fine particles suspended in the solution. Approximately 0.5mL of the solution containing the fine particles were injected into a0.2 micrometer PTFE filter (Nalgene, 25 mm). Normal saline was infusedthrough the filter via a 3M® 3000 Modular Infusion Pump at a rate of 2ml/hr for approximately 7 days. This was to wash away the lidocaine thatwas not incorporated in to the Medisorb matrix and particles smallerthan 0.2 micrometer, while lidocaine-polymer particles bigger than 0.2micrometer were trapped in the filter. The particles slowly degraded dueto hydrolysis and thus gradually releases lidocaine to the salinepassing through the filter.

[0138] A blunt needle was tightly attached to the exit end of thefilter, and a thin plastic tube was attached to the blunt needle.Filtered solution from the distal end of the thin plastic tube wascollected according the following steps:

[0139] Step 1: Filter at room temperature (about 24° C.) and collect thefiltered solution into a glass vial for approximately 1 hour.

[0140] Step 2: Immerse the filter into a 36° C. (approximate) waterbath, wait approximately 1 hour, and collect the filtered solution fromthe thin tube for approximately 1 hour.

[0141] Step 3: Increase the temperature of the water bath to about 44°C., wait approximately 1 hour, and collect the filtered solution forapproximately 1 hour.

[0142] Step 4: Take the filter out of the water bath and leave at roomtemperature (about 24° C.) for approximately 0.5 hours, collect thefilter solution for approximately 1 hour.

[0143] Step 5: Repeat Step 4 after approximately 2 hours.

[0144] Saline was infused through the filter at the 2 mL/hour rate forthe entire experiment. The solution coming out of the thin plastic tubduring non-collecting time were discarded. Concentrations of lidocainein above collected solutions were determined by an HPLC (HighPerformance Liquid Chromatography) method.

[0145] Lidocaine release rates from the polymer matrix at differenttemperatures were calculated from lidocaine concentrations in thecollected samples. The release rates are shown in Table E, as follows:TABLE E Lidocaine Release Rate Step Temperature (mcg/hour) 1 24° C. 0.362 36° C. 0.61 3 44° C. 1.59 4 24° C. 0.47 5 24° C. 0.38

[0146] As the results demonstrate, the lidocaine release rate increasedwhen temperature at the filter (and hence the temperature of thelidocaine-polymer particles) was increased, and decreased when thetemperature was decreased. Although the filter temperature in Steps 4and 5 were the same, the lidocaine release rate in Step 5 was lower thanthat in Step 4, and approaches that in Step 1.

[0147] Although the total quantities of Medisorb and lidocaine in thefilter were not measured, the relative differences in the lidocainerelease rates at different temperatures demonstrate that lidocainerelease rate from Medisorb polymer increases with temperature. Thefinding that lidocaine release rate in Step 5 was lower than that inStep 4 suggest that the release rate decreases gradually after thetemperature is lowered.

[0148] Since the degradation (hydrolysis) of Medisorb polymer isbelieved to control the release rates, these results suggest thatMedisorb polymer degradation rate increases with increasing temperature.This suggests that the release rate of any drug incorporated in theMedisorb matrix (or other similar materials) and injected into the bodycan be increased by increasing temperature. In addition to increasinghydrolysis rate of the Medisorb-lidocaine particles, heat is alsoexpected to increase the flow of body fluid surrounding the particles inthe storage site in actual application, which should cause an additionalincrease in the drug absorption rate.

[0149] Another experiment was conducted on the Medisorb (same type asdiscussed above). A first sample of the Medisorb (transparent beads)weighing 0.1024 grams was placed in a first glass vial with 9.9024 gramsof 0.9% sodium chloride injection solution. The first glass vial wassealed with parafilm and placed in an oven which maintained atemperature of about 43° C. A second sample of the Medisorb weighing0.1028 grams was placed in a second glass vial with 9.9167 grams of 0.9%sodium chloride injection solution. The second glass vial was sealedwith parafilm and placed in a room with a temperature of about 23° C.

[0150] After 29 days, few visible change had occurred to the Medisorbheld at room temperature (second sample). However, the Medisorb held atabout 43° C. changed from a transparent material to a milky-white colorwith smoothed edges. The Medisorb beads also appeared smaller than theoriginal size. This simple experiment demonstrates that the degradationrate of the Medisorb polymer increases with increasing temperature.

EXAMPLE 19

[0151] Still another example of storage site absorption using theembodiment of the present invention illustrated in FIGS. 1 and 2consists of a patient or care giver implanting a solid piece (i.e.,plate, rod, or the like) made of a biocompatible, bioerodablematerial(s), such as listed in Example 16, under the skin surface. Byway of example, insulin can be incorporated into such a material. Theinsulin-containing solid piece is implanted into a diabetic patient in aposition within 3 cm, preferably within 1 cm, and most preferably within0.3 cm, from the skin. The insulin release rate from the solid piece isdesigned to be sufficient to provide the baseline insulin need forextended period of time (e.g., a few months). Before each meal, thepatient places the temperature control apparatus 100, preferably with apre-determined heating duration, on to the skin site under which thesolid piece resides. The heat from the temperature control apparatus 100increases the flow of blood or other body fluid surrounding the solidpiece, thus increases the erosion/degradation of the solid piece anddelivers extra insulin to the systemic circulation to suppress the sugarfrom the meals. After the pre-determined duration of temperature controlapparatus 100 is over or after the patient discontinues the heating fromthe temperature control apparatus 100, the erosion/degradation rate ofthe solid piece gradually returns to normal, as does the insulin releaserate.

[0152] Furthermore, such a system can be used with testosterone in asolid piece which implanted in the patient's skin. Preferably, thetemperature control apparatus 100 is designed to last substantiallylonger (i.e., approximately 6-10 hours). The patent applies thetemperature control apparatus 100 on the skin site under which the solidpiece resides to obtain increased testosterone levels in the blood inthe period from morning to evening when testosterone is most needed.

[0153] Although only a small number of drugs have been disclosed inExamples 13-18, any drug used in a treatment that fits the followingdescription may potentially benefit from the methods: 1) the treatmentrequires that the drug have a baseline deliver rate over long treatmentduration (such as longer than a day, preferably over a week), and 2) thetreatment requires the drug to have increased delivery rates for aperiod or periods of time during the long treatment duration. A varietyof drugs and drug classes can be utilized with such treatments. Thedrugs include, but are not limited to, nicotine, testosterone,estradiol, nitroglycerin, clonidine, dexamethasone, tetracaine,lidocaine, fentanyl, sufentanil, progestrone, insulin, prilocaine,bupivacaine, sumatriptan, and dihydroergotamine. The drug classesinclude, but are not limited to, androgen, estrogen, non-steroidalanti-inflammatory agents, anti-hypertensive agents, analgesic agents,anti-depressants, antibiotics, anti-cancer agents, local anesthetics,antiemetics, anti-infectants, contraceptives, anti-diabetic agents,steroids, anti-allergy agents, anti-migraine agents, agents for smokingcessation, anti-asthma agents, and anti-obesity agents.

EXAMPLE 20

[0154] Still yet another example of storage site absorption using theembodiment of the present invention illustrated in FIGS. 1 and 2consists of a patient or care giver imbedding a drug into the depotsite. By way of example, a care giver can embed an anti-migraine drug,such as a powder form of dihydroergotamine, sumatriptan, or ergotamine,by hitting the drug into a depot site under the skin at high speed (suchas by a device manufactured by Powderject Pharmaceutical, UnitedKingdom) when a patient feels an episode of migraine headache isimminent. With the Powderjet device, the drug powder is accelerated to aspeed higher than the speed of sound and hit into the skin. Atemperature control apparatus 100, preferably lasting approximately 1hour, is immediately applied on the skin over the location of theembedded drug. The heat from the temperature control apparatus 100increases the speed of the body fluid flow surrounding the anti-migrainedrug and carries the anti-migraine drug into the systemic circulationfaster. As a result, therapeutical blood concentrations of theanti-migraine drug is reached earlier and in time to treat the migraineheadache.

[0155] This technique may also be used to deliver a preventativebaseline release rate of a drug, such as anti-migraine drug ornitroglycerine. A heating patch is then applied to release extra drugwhen a medical episode begins.

[0156] It is, of course, understood that the heating devices discussedabove could be replaced by an infrared heating device or a microwaveheating device with a feedback mechanism. All the controls andvariations in controls discussed above would apply to such devices.

EXAMPLE 21

[0157] Ultrasound can be used to increase release rate of injectedcontrolled release drug formulations, particularly, when the controlledrelease formulations are in the form of relatively large particles(i.e., 25 μm or larger). The controlled release formulation is injectedinto the patient's tissues within 3 cm, preferably within 1 cm, and mostpreferably 0.3 cm from the skin. The erosion/degradation rate of theparticles determines the rate of release of the drug, and the steadystate release rate of the drug is designed to deliver a therapeuticallevel of drug to the patient. For analgesic drugs, the steady staterelease rate is usually slightly below that needed to treat an averageperson's post-operative pain. For a particular patient in whom thesteady state release rate is not sufficient (because of hispharmacokinetics and/or level of pain), an ultrasound is directed intoformulation and breaks the particles into smaller ones (this requiresthat the particles are capable of being broken by ultrasound).

[0158] This increases the surface area of the formulation exposed to thesurrounding body fluid, and hence increases the release rate for therest of the administration. This method allows the administration of alow release rate formulation which is safe, and then increasing therelease rate for patients who need higher delivery rates. The intensity,frequencies, and duration of ultrasound can be chosen to increase therelease rate to proper levels. Exemplary ultrasound treatment anddevices can be found in U.S. Pat. No. 4,948,587 issued Aug. 14, 1998 toKost et al., hereby incorporate herein by reference.

EXAMPLE 22

[0159] The generation of an electric potential on a portion of apatient's body can be used to increase release rate of injectedcontrolled release drug formulations, particularly, when the controlledrelease formulations exist in ionized form in the formulations and/orsurrounding body fluid. For example, when a controlled release insulinis injected into a diabetic patient's skin, the normal release rate ofinsulin from this formulation is controlled by the dissolution rate ofthe particles in which insulin resides wherein the normal release rateprovides an adequate baseline insulin level in the patient. As shown inFIG. 26, the patient places a first electrode 262 on the skin 134 overthe injection site of the controlled release insulin formulation 264. Asecond electrode 266 is placed on a skin 134 in a position near theinjection site of the controlled release insulin formulation 264 (i.e.,at least a few centimeters away). Before each meal when the patientneeds to increase his blood insulin level to suppress sugar from themeal, the patient connects the first electrode 262 and the secondelectrode 266 with wires 268 and 270, respectively, to an electriccurrent generating device 272. The electric current generating device272 introduces an electrical potential between the first electrode 262and the second electrode 266. Preferably, with the use of insulin, theelectrical amperage should be in the range of between about 0.2 and 4mA. Because at the physiological pH, insulin molecules carry netnegative electric charges, the first electrode 262 should have anegative charge which pushes the negatively charged insulin away fromthe body fluid surrounding the formulation and into the systemiccirculation 254. This makes the insulin release faster. Preferably, theintensity and duration of the current can be altered with the electriccurrent generating device 272 to deliver the requisite therapeuticamount of extra insulin.

EXAMPLE 23

[0160] The generation of a vibration over the injection site ofcontrolled release drug formulations can be used to increase releaserate of the formulations, particularly, when the controlled releaseformulations have limited solubility in body fluid or with solidformulations whose erosion/degradation speed can be significantlyincreased by increasing flow/exchange of body fluid surrounding thesolid formulation. For example, when a controlled release insulin isinjected into a diabetic patient's skin, the normal release rate ofinsulin from this formulation is controlled by the erosion/degradationor dissolution rate of the particles in which insulin resides whereinthe normal release rate provides an adequate baseline insulin level inthe patient. As shown in FIG. 27, before each meal, the patient places avibration generating device 282 on the skin 134 over the injection siteof the controlled release insulin formulation 264. The vibrationgenerating device 282, preferably, delivers vibration of between about20 and 400 Hz. The vibration agitates the body fluid (not shown)surrounding the controlled release insulin 264 and increases itscirculation. As a result, more insulin is released from the controlledrelease insulin formulation 264 to the systemic circulation 254 shortlybefore the meal to suppress the sugar from the meal. Preferably, theintensity and duration of the vibration can be altered with thevibration generating device 282 to deliver the requisite therapeuticamount of extra insulin.

[0161] Although only a few drugs have been disclosed in Examples 19-22,any drug used in a treatment that fits the following description maypotentially benefit from the physical methods for inducing increasedrelease: 1) the treatment requires that the drug have a baseline deliverrate over long treatment duration (such as longer than a day, preferablyover a week), 2) the treatment requires the drug to have increaseddelivery rates for a period or periods of time during the long treatmentduration, and 3) the formulations respond to the one or more of thephysical methods for inducing increased release. A variety of drugs anddrug classes can be utilized with such treatments. The drugs include,but are not limited to, nicotine, testosterone, estradiol,nitroglycerin, clonidine, dexamethasone, tetracaine, lidocaine,fentanyl, sufentanil, progestrone, insulin, prilocaine, bupivacaine,sumatriptan, and dihydroergotamine. The drug classes include, but arenot limited to, androgen, estrogen, non-steroidal anti-inflammatoryagents, anti-hypertensive agents, analgesic agents, anti-depressants,antibiotics, anti-cancer agents, local anesthetics, antiemetics,anti-infectants, contraceptives, anti-diabetic agents, steroids,anti-allergy agents, anti-migraine agents, and agents for smokingcessation.

EXAMPLE 24

[0162] Another example of the present invention comprises using atemperature control apparatus 300, similar to that shown in FIG. 23,which is capable of heating and cooling, such that the rate ofabsorption of injected controlled release drug formulation can beincreased or decreased, as needed.

[0163] For example, when a controlled release drug formulation isinjected into a patient's skin, the normal release rate of the drug fromthis formulation is controlled by the erosion/degradation rate of theparticles in which the drug resides wherein the normal release rateprovides an adequate baseline drug level in the patient. As shown inFIG. 28, if the level of the drug in the patient's system requiresadjusting, the temperature control apparatus 300 is placed on the skin134 over the injection site of the controlled release drug formulation302. Heating will result in an increase in drug absorption (aspreviously discussed) and cooling will reduce drug absorption to preventoverdose. FIG. 23 illustrates the temperature control apparatus 300 as athermoelectric module which is be used for both heating or cooling. Thetemperature control apparatus 300 functions as a small heat pump,wherein a low voltage DC power source 304 provides a current in onedirection 306 to a thermoelectric unit 310 which results in heating on afirst side 308 (preferably a ceramic substrace) of the temperaturecontrol apparatus 300 and cooling on a second side 312 (preferably afinned dissipation structure) of the temperature control apparatus 300.If the current direction is reversed, the first side 308 will cool andthe second side will heat. The temperature control apparatus 300 may becontrol with a closed loop temperature controller, as shown previouslyin FIG. 24.

[0164] A variety of drugs and drug classes can be utilized with suchtreatments. The drugs include, but are not limited to, nicotine,nitroglycerin, clonidine, dexamethasone, fentanyl, sufentanil, andinsulin. The drug classes include, but are not limited to, androgen,non-steroidal anti-inflammatory agents, anti-hypertensive agents,analgesic agents, anti-depressants, anti-cancer agents, anti-diabeticagents, steroids, anti-migraine agents, and agents for smokingcessation.

EXAMPLE 25

[0165] Another example of the present invention comprises using thetemperature control apparatus 300, as shown in FIG. 23, or any devicewhich is capable of cooling the skin in conjunction with an injectableliquid drug delivery formulation containing thermal gel.

[0166] The main difference between a thermal gel and a regular gel isthat a thermal gel is a liquid in room temperature (i.e., about 20-25°C.) and is a gel at body temperature (i.e., about 37° C.), whereas, withregular gel, the viscosity of the gel generally lowers with increasingtemperature. Thus, while the thermal gel is at room temperature (i.e.,in liquid form), a drug formulation is mixed into the thermal gel. Thethermal gel/drug mixture may then be easily drawn into a syringe andinjected to the patient. Once in the patient's body, the thermalgel/drug mixture quickly solidifies into a gel. The gel then dissolvesover time releasing the drug formulation into the patient systemiccirculation.

[0167] Using a cooling device, such as the temperature control apparatusshown in FIG. 23, the thermal gel/drug mixture which has solidifiedunder the skin can be cooled to revert the gel back into a liquid. In aliquid state, the drug formulation diffusion rate and release rateincrease, thereby increasing the drug formulation present in thepatient's systemic circulation when needed.

[0168] An example of a thermal gel is Smart Hydrogel™ developed by GelScience/GelMed and consists of an entangled network of two randomlygrafted polymers. One polymer is poly(acrylic acid) which is bioadhesiveand pH-responsive. The other polymer is a triblock copolymer containingpoly(propylene oxide) (“PPO”) and poly(ethylene oxide) (“PEO”) segmentsin the sequence PEO-PPO-PEO.

[0169] An example of using the present invention with a thermal gel isthe delivery of additional insulin to a diabetic patient prior to theintake of food. The thermal gel containing the insulin can be injectedsubcutaneously in order to form a gel to release a continuous baselinedosage of insulin. At a meal when insulin is needed to absorb extrasugar in the circulation, the patient can apply the cooling device onthe skin adjacent the injection site and cool the injection site to atemperature below the gelling temperature of the thermal gel/insulinmixture. The gel will, of course, become a liquid and increase theinsulin level in the patient's body to compensated for the ingestedmeal. This process can be repeated many times until the injected thermalgel/insulin mixture is gone. The advantage of this drug delivery systemis that the diabetic patient can control insulin delivery during thecourse of a few days, even a few weeks, with only one injection.

EXAMPLE 26

[0170] As shown in FIG. 29, an insulating material can be incorporatedwith the controlled temperature apparatus to assist in not onlyminimizing the temperature variation, but also increasing thetemperature of the DDDS and the skin under it (by decreasing heat loss),each of which tend to increase dermal drug absorption.

[0171]FIG. 29 illustrates a configuration similar to that illustrated inFIG. 4 wherein the temperature control apparatus 100 of FIG. 2 isattached to the DDDS 120 of FIG. 3. The DDDS 120 attached to a portionof the skin 134 of a patient. An insulating sleeve 350 abuts the skin134 and encases a substantial portion of the temperature controlapparatus 100 and the DDDS 120.

[0172]FIG. 30 illustrates another insulating sleeve 360 made of aninsulating material, such as closed-cell foam tape, with adhesive edges362 attached to a patient's skin 134, slightly larger than and coveringa DDDS 364. FIG. 31 illustrates the insulating sleeve 360 covering aheating apparatus 366 and the DDDS 364 attached to a patient's skin 134.FIG. 32 illustrates the insulating sleeve 360 covering an area over theskin 134 where an injected/implanted/ controlled/extended release drugformulation 368 has been located.

EXAMPLE 27

[0173] Another application of the present invention involves the use ofa heating device, such as discussed above, in conjunction with a typicalliquid drug injection. For some drugs, increased speed of absorptioninto the systemic circulation after they are injected into the body mayprovide treatment to the patients. For instance, to be effective, theanti-migraine drug, dihydroergotamine, must reach an effectiveconcentration level in the blood stream within a certain amount of timefrom the onset of the migraine attack or the drug will be ineffective.Currently, a drug's absorption into the patient's systemic circulationcannot be altered after it is injected. Thus, the controlled heatingaspect of the present invention can be used to increase the absorptionspeed of subcutaneously and intramuscularly injected drugs.

[0174] For example, after a drug is injected subcutaneously orintramuscularly, a heating patch, such as described in the aboveexamples, may be placed on the skin under which the injected drugresides. The heating increases the circulation of body fluid surroundingthe injected drug, increases the permeability of blood vessel walls inthe surrounding tissue, and, thus, results in increased speed ofabsorption of the drug into the systemic circulation.

[0175] Such a method would be useful for drugs which are injected into apart of the body that can be heated by a heating means on or outside theskin and whose effect can be improved by increased absorption speed intothe systemic circulation or deeper tissues. Such drugs may include;anti-migraine agents, anti-hypertensive agents, analgesics, antiemetics,cardiovascular agents. Specific drugs may include dihydroergotamine,ergotamine, sumatriptan, rizatriptan, zolmitriptan, and other selective5-hydroxytryptamine receptor subtype agonists, morphine and othernarcotic agents, atropine, nitroglycerin, fentanyl, sufentanil,alfentanil, and meperidine.

[0176] Since increased absorption speed into the systemic circulationusually can cause higher peak concentrations in the blood, thistechnology may also be used to increase peak blood concentrations ofdrugs that are injected subcutaneously and intramuscularly.

[0177] Some drugs need to be injected intravenously because systemicabsorption for subcutaneous and intramuscular injections take too longto take effect. However, intravenous injection is more difficult toperform and involves more risks. With the use of the present invention,the absorption speed of some drugs may be increased enough so thatsubcutaneous or intramuscular injection can provide sufficient speed ofabsorption. Therefore, this technology may also be used for replacingintravenous injections with subcutaneous or intramuscular injections forsome drugs.

[0178] As a specific example, a patient may inject himself withsumatriptan or dihydroergotamine subcutaneously after he feels amigraine attack. He then removes a heating patch containing a heatgenerating medium comprising iron powder, activated carbon, water,sodium chloride, and sawdust (similar to Example 1) out of its air-tightcontainer and places it over the injection site. The heating patchquickly increases the temperature of the skin under the heating patchinto a narrow range of 39-43° C. and maintains it there for at least 15minutes. The circulation speed of the body fluid surrounding theinjected drug and the permeability of the blood vessels in thesurrounding tissues are both increased by the heating. As a result, thedrug enters the systemic circulation and reaches the acting site morerapidly, and the patient receives more rapid and/or better control ofthe migraine attack.

[0179] In another example, a nurse can inject morphine into a patient'smuscle tissue to treat severe pain. The nurse then places a heatingpatch, as describe above, over the injection site. The speed of morphineabsorption into the systemic circulation is increased as previouslydiscussed. As a result, the patient receives more rapid and/or betterpan control.

EXAMPLE 28

[0180] Another application of the present invention involves the use ofa heating device, such as discussed above, to mimic circadian patterns.For example, testosterone or its derivatives, such as testosteroneenanthate and testosterone cypionate, can be injected intramuscularlyinto men to substitute or replace diminished or absent naturaltesticular hormone. Testosterone enanthate and testosterone cypionateare preferred over testosterone, as they have longer duration of actionthan testosterone. However, it is understood that testosterone or itsderivative, such a testosterone ester, may be incorporated into acontrolled release polymer matrix, such as homopolymer or copolymer oflactic and glycolic acid, preferably poly(DL-lactide),poly(DL-lactide-co-glycolide), and poly(DL-lactide-co-(- caprolactone)),to increase the duration of action. Following intramuscular injection,testosterone enanthate is absorbed gradually from the lipid tissue phaseat the injection site to provide a duration of action of up to 2-4weeks. However, natural blood testosterone concentrations in healthy manare higher in a day and lower in the night. So blood testosteroneconcentrations obtained from injected testosterone derivatives do notmimicking the natural circadian pattern.

[0181] By way of example, a patient can inject testosterone enanthateeither subcutaneously or intramuscularly (if intramuscularly, theinjection should be relatively close to the skin surface). The patientthen places a heating patch on the injection site every morning (untilall the injected testosterone enanthate is depleted). The heating patchquickly increases the temperature of the injection site to a narrowrange, and maintains it therefore a desirable duration of time (i.e.,about 8 hours). They heating causes increased release of testosteroneenanthate and/or increased rate of conversion from testosteroneenanthate to testosterone, and, thus, higher blood testosteroneconcentrations. The “used-up” patch is removed before a new heatingpatch is placed on the same. Using this intermittent heat applicationtechnique, blood testosterone concentrations are low in the night andhigh in the day, thus mimicking the natural circadian pattern.

[0182] Having thus described in detail preferred embodiments of thepresent invention, it is to be understood that the invention defined bythe appended claims is not to be limited by particular details set forthin the above description as many apparent variations thereof arepossible without departing from the spirit or scope thereof.

What is claimed is:
 1. A method of controlled delivery of analgesicthrough a patient's skin to a patient's systemic circulation comprising:delivering an analgesic through the skin of patient at a delivery siteon the skin; applying a temperature modification apparatus proximate tothe delivery site on the skin; and heating said skin with thetemperature modification apparatus.
 2. A method of claim 1, wherein saidtemperature modification apparatus comprises: a shallow chamber definedby a cover, a frame of air impermeable material, and a bottom; a heatgenerating medium disposed within said chamber; and means to affix saidshallow chamber onto said human skin.
 3. A method of claim 2, whereinsaid means to affix said shallow chamber onto human skin comprises anadhesive disposed on said chamber such that said adhesive affixes saidchamber to human skin, when said adhesive is in contact with human skin.4. The method of claim 2, wherein said temperature modificationapparatus further comprises means to affix said shallow chamber to adermal drug delivery system, said mans to affix to a dermal drugdelivery system being an adhesive that has the characteristic of beingless adhesive to the dermal drug delivery system than the means to affixto human skin is adhesive.
 5. The method as claimed in claim 2, whereinsaid heat generating medium comprises activated carbon and iron in apredetermined ratio.
 6. The method as claimed in claim 4, said heatgenerating medium further comprising sodium chloride and sawdust.
 7. Themethod as claimed in claim 1, wherein the temperature modificationapparatus further comprises a substantially two-dimensional devicecomprising a resistor layer capable of generating heat when suppliedwith electricity, means to affix said substantially two-dimensionaldevice, and means to supply electric currents to said resistor layer. 8.The method as claimed in claim 7, wherein said means to supply electriccurrent to said resistor layer comprises means to regulate the intensityof electric current supplied to said resistor layer.
 9. The method asclaimed in claim 7, wherein the means to regulate the intensity ofelectric current is capable of regulating the intensity of electriccurrent according to the temperature of said substantiallytwo-dimensional device.
 10. The method as claimed in claim 9, whereinsaid means to regulate said intensity of said electric current comprisesa thermistor.
 11. The method as claimed in claim 1, further comprisingthe step of discontinuing said heating of said skin when continuation ofsaid heating would be injurious to the patient.
 12. The method asclaimed in claim 1, wherein the step of said heating of said skincomprises discontinuing said heating when continuation of said heatingwould be injurious to the patient.
 13. The method as claimed in claim 1,wherein the step of said heating said skin includes heating saidanalgesic.
 14. The method as claimed in claim 1, wherein the step ofheating further comprises heating a transdermal analgesic deliverysystem to a temperature of about between 38 and 45° C.
 15. The method asclaimed in claim 1, further comprising the step of discontinuing saidheating of said skin of said human body with said temperaturemodification apparatus at a time when a patient's break-through paindiminishes.
 16. The method as claimed in claim 1, wherein thetemperature modification apparatus is capable of generating controlledheat, said controlled heat having a predetermined temperature range anda predetermined time duration.
 17. The method as claimed in claim 1,wherein said temperature is increased to about 60° C.
 18. The method inclaim 1, wherein the temperature range is between about 38 to about 45°C.
 19. The method as claimed in claim 1, wherein the temperature rangeis about 39 to about 44° C.
 20. The method of claim 2, wherein saidcover comprises an air impermeable material, said material defining apredetermined number of openings having a predetermined size.
 21. Theapparatus as claimed in claim 2, wherein said cover comprises an airimpermeable material defining at least one opening covered with amembrane, said membrane having a predetermined air pereability.
 22. Adrug delivery system comprising: a transdermal drug patch for deliveringan analgesic transdermally when said patch is applied to a patient'sskin, and a temperature control apparatus secured to said patch and saidtemperature control apparatus being capable of heating said patch andsaid patient's skin proximate said patch, when said patch is disposed onsaid patient's skin and when said temperature control apparatus issecured to said patch.